Repeat placental growth factor-based testing in women with suspected preterm pre-eclampsia (PARROT-2): a multicentre, parallel-group, superiority, randomised controlled trial.

BACKGROUND: Placental growth factor (PlGF)-based testing has high diagnostic accuracy for predicting pre-eclampsia needing delivery, significantly reducing time to diagnosis and severe maternal adverse outcomes. The clinical benefit of repeat PlGF-based testing is unclear. We aimed to determine whether repeat PlGF-based testing (using a clinical management algorithm and nationally recommended thresholds) reduces adverse perinatal outcomes in pregnant individuals with suspected preterm pre-eclampsia. METHODS: In this multicentre, parallel-group, superiority, randomised controlled trial, done in 22 maternity units across England, Scotland, and Wales, we recruited women aged 18 years or older with suspected pre-eclampsia between 22 weeks and 0 days of gestation and 35 weeks and 6 days of gestation. Women were randomly assigned (1:1) to revealed repeat PlGF-based testing or concealed repeat testing with usual care. The intervention was not masked to women or partners, or clinicians or data collectors, due to the nature of the trial. The trial statistician was masked to intervention allocation. The primary outcome was a perinatal composite of stillbirth, early neonatal death, or neonatal unit admission. The primary analysis was by the intention-to-treat principle, with a per-protocol analysis restricted to women managed according to their allocation group. The trial was prospectively registered with the ISRCTN registry, ISRCTN 85912420. FINDINGS: Between Dec 17, 2019, and Sept 30, 2022, 1253 pregnant women were recruited and randomly assigned treatment; one patient was excluded due to randomisation error. 625 women were allocated to revealed repeat PlGF-based testing and 627 women were allocated to usual care with concealed repeat PlGF-based testing (mean age 32·3 [SD 5·7] years; 879 [70%] white). One woman in the concealed repeat PlGF-based testing group was lost to follow-up. There was no significant difference in the primary perinatal composite outcome between the revealed repeat PlGF-based testing group (195 [31·2%]) of 625 women) compared with the concealed repeat PlGF-based testing group (174 [27·8%] of 626 women; relative risk 1·21 [95% CI 0·95-1·33]; p=0·18). The results from the per-protocol analysis were similar. There were four serious adverse events in the revealed repeat PlGF-based testing group and six in the concealed repeat PlGF-based testing group; all serious adverse events were deemed unrelated to the intervention by the site principal investigators and chief investigator. INTERPRETATION: Repeat PlGF-based testing in pregnant women with suspected pre-eclampsia was not associated with improved perinatal outcomes. In a high-income setting with a low prevalence of adverse outcomes, universal, routine repeat PlGF-based testing of all individuals with suspected pre-eclampsia is not recommended. FUNDING: Tommy's Charity, Jon Moulton Charitable Trust, and National Institute for Health and Care Research Guy's and St Thomas' Biomedical Research Centre.

Planned delivery or expectant management for late preterm pre-eclampsia in low-income and middle-income countries (CRADLE-4): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality. Evidence regarding interventions in a low-income or middle-income setting is scarce. We aimed to evaluate whether planned delivery between 34+ 0 and 36+ 6 weeks' gestation can reduce maternal mortality and morbidity without increasing perinatal complications in India and Zambia. METHODS: In this parallel-group, multicentre, open-label, randomised controlled trial, we compared planned delivery versus expectant management in women with pre-eclampsia from 34+ 0 to 36+ 6 weeks' gestation. Participants were recruited from nine hospitals and referral facilities in India and Zambia and randomly assigned to planned delivery or expectant management in a 1:1 ratio by a secure web-based randomisation facility hosted by MedSciNet. Randomisation was stratified by centre and minimised by parity, single-fetus pregnancy or multi-fetal pregnancy, and gestational age. The primary maternal outcome was a composite of maternal mortality or morbidity with a superiority hypothesis. The primary perinatal outcome was a composite of one or more of: stillbirth, neonatal death, or neonatal unit admission of more than 48 h with a non-inferiority hypothesis (margin of 10% difference). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The trial was prospectively registered with ISRCTN, 10672137. The trial is closed to recruitment and all follow-up has been completed. FINDINGS: Between Dec 19, 2019, and March 31, 2022, 565 women were enrolled. 284 women (282 women and 301 babies analysed) were allocated to planned delivery and 281 women (280 women and 300 babies analysed) were allocated to expectant management. The incidence of the primary maternal outcome was not significantly different in the planned delivery group (154 [55%]) compared with the expectant management group (168 [60%]; adjusted risk ratio [RR] 0·91, 95% CI 0·79 to 1·05). The incidence of the primary perinatal outcome by intention to treat was non-inferior in the planned delivery group (58 [19%]) compared with the expectant management group (67 [22%]; adjusted risk difference -3·39%, 90% CI -8·67 to 1·90; non-inferiority p<0·0001). The results from the per-protocol analysis were similar. There was a significant reduction in severe maternal hypertension (adjusted RR 0·83, 95% CI 0·70 to 0·99) and stillbirth (0·25, 0·07 to 0·87) associated with planned delivery. There were 12 serious adverse events in the planned delivery group and 21 in the expectant management group. INTERPRETATION: Clinicians can safely offer planned delivery to women with late preterm pre-eclampsia, in a low-income or middle-income country. Planned delivery reduces stillbirth, with no increase in neonatal unit admissions or neonatal morbidity and reduces the risk of severe maternal hypertension. Planned delivery from 34 weeks' gestation should therefore be considered as an intervention to reduce pre-eclampsia associated mortality and morbidity in these settings. FUNDING: UK Medical Research Council and Indian Department of Biotechnology.

Breastfeeding behaviours in women with obesity; associations with weight retention and the serum metabolome: a secondary analysis of UPBEAT.

BACKGROUND/OBJECTIVES: Maternal obesity is associated with a decreased intention and initiation of breastfeeding as well as a shortened duration of breastfeeding. This analysis was undertaken to identify breastfeeding behaviours, and relationships with maternal anthropometry and the serum metabolome at 6-months postpartum in an ethnically diverse cohort of women with obesity. SUBJECTS/METHODS: A cohort analysis of 715 women from the UK Pregnancies Better Eating and Activity Trial (UPBEAT); a multi-centre randomised controlled trial of an antenatal lifestyle intervention in women with obesity. Maternal data were collected in early pregnancy and included body mass index (BMI), socio-demographic characteristics and anthropometry. At 6-months postpartum, breastfeeding behaviours, anthropometry and 158 maternal metabolic measures from blood samples were recorded. Kaplan-Meier curves of breastfeeding duration were constructed and were stratified by obesity class (I: BMI 30.0-34.9 kg/m2, II: 35.0-39.9 kg/m2, III: ≥40.0 kg/m2). Relationships between breastfeeding behaviours, socio-demographic characteristics, the metabolome, and anthropometry were determined using regression analyses. RESULTS: Eighty-two percent (591/715) of the cohort-initiated breastfeeding and at the 6-month follow-up 40% (283/715) were breastfeeding exclusively or partially. Duration of exclusive breastfeeding decreased with increasing BMI: Compared to BMI class I (mean 90.4 ± 64 days) the difference in mean for classes II and III were -15.8 days (95% confidence interval: -28.5, -3.1, p < 0.05) and -16.7 (95% CI: -32.0 to -1.35, p < 0.05), respectively. Compared to no breastfeeding, any breastfeeding at 6-months postpartum was associated with improvements in metabolites towards a healthier profile, reduced weight retention by -1.81 kg (95% CI -0.75, -2.88, p < 0.05 ) and reduced anthropometric measures, including mid-upper arm and hip circumferences. The breastfeeding related changes in anthropometry were not evident in women of Black ethnicity. CONCLUSIONS: Greater emphasis on enabling breastfeeding for women with obesity could improve duration, women's weight management and metabolic health. The lack of breastfeeding related anthropometric effects in Black women requires further investigation. CLINICAL TRIAL REGISTRY: ISRCTN reference 89971375.

Serum bile acid measurements in women of European and South Asian ethnicity with or without gestational diabetes mellitus: A cohort study.

OBJECTIVE: Investigation of serum bile acid profiles in pregnancies complicated by gestational diabetes mellitus (GDM) in a multi-ethnic cohort of women who are lean or obese. DESIGN: Prospective cohort study. SETTING: UK multicentre study. POPULATION: Fasting serum from participants of European or South Asian self-reported ethnicity from the PRiDE study, between 23 and 31 weeks of gestation. METHODS: Bile acids were measured using ultra-performance liquid chromatography-tandem mass spectrometry. Log-transformed data were analysed using linear regression in STATA/IC 15.0. MAIN OUTCOME MEASURES: Total bile acids (TBAs), C4, fasting glucose and insulin. RESULTS: The TBAs were 1.327-fold (1.105-1.594) increased with GDM in European women (P = 0.003). Women with GDM had 1.162-fold (1.002-1.347) increased levels of the BA synthesis marker C4 (P = 0.047). In South Asian women, obesity (but not GDM) increased TBAs 1.522-fold (1.193-1.942, P = 0.001). Obesity was associated with 1.420-fold (1.185-1.702) increased primary/secondary BA ratio (P < 0.001) related to 1.355-fold (1.140-1.611) increased primary BA concentrations (P = 0.001). TBAs were positively correlated with fasting glucose (P = 0.039) in all women, and with insulin (P = 0.001) and the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (P = 0.001) in women with GDM. CONCLUSIONS: Serum BA homeostasis in late gestation depends on body mass index and GDM in ethnicity-specific ways. This suggests ethnicity-specific aetiologies may contribute to metabolic risk in European and South Asian women, with the relationship between BAs and insulin resistance of greater importance in European women. Further studies into ethnicity-specific precision medicine for GDM are required.

Associations between maternal diet, family eating habits and preschool children's dietary patterns: insights from the UPBEAT trial.

BACKGROUND: Dietary behaviours in early life often track across the life course, influencing the development of adverse health outcomes such as obesity and cardiovascular disease. This study aimed to explore the between dietary patterns (DP) in preschool children and maternal DP and family eating habits. METHODS: We conducted a secondary analysis of 488 mother-child pairs from the UK pregnancy Better Eating and Activity Trial (UPBEAT) at 3-year follow-up. Previously published DP from mothers and children (derived from food-frequency questionnaires and exploratory factor analysis) were used. Mothers' DP were "Fruits-Vegetables", "African-Caribbean", "Processed and Snacks", and children's DP were "Prudent", "Processed-Snacking", and "African-Caribbean". Family meal environments were evaluated using a 5-point Likert scale. RESULTS: Linear regression models revealed that child's prudent pattern was positively associated with maternal Fruits-Vegetables (B = 0.18 (0.08, 0.27)), Snacks patterns (B = 0.10 (0.01, 0.18)), and eating the same foods during meals (B = 0.25 (0.07, 0.43)). Child's Processed-Snacking pattern was directly associated with maternal Processed (B = 0.22 (0.13, 0.30)) and Snacks (B = 0.27 (0.18, 0.36)) patterns, receiving food as reward (B = 0.22 (0.04, 0.39)) and watching TV during meals (B = 0.27 (0.09, 0.45)). Finally, the child African-Caribbean pattern was directly associated with that from the mother (B = 0.41 (0.33, 0.50)) and watching TV during meals (B = 0.15 (0.09, 0.30)), and inversely associated with maternal processed (B=-0.09 (-0.17, -0.02)) and snacking (B=-0.08 (-0.15, -0.04)) patterns. CONCLUSIONS: Unhealthy dietary patterns in childhood are directly linked to similar maternal patterns and family meal behaviours, such as television viewing and food rewards. These findings highlight targetable behaviours for public health interventions.

Adrenal volumes in fetuses delivering prior to 32 weeks' gestation: An MRI pilot study.

INTRODUCTION: Spontaneous preterm birth prior to 32 weeks' gestation accounts for 1% of all deliveries and is associated with high rates of morbidity and mortality. A total of 70% are associated with chorioamnionitis which increases the incidence of morbidity, but for which there is no noninvasive antenatal test. Fetal adrenal glands produce cortisol and dehydroepiandosterone-sulphate which upregulate prior to spontaneous preterm birth. Ultrasound suggests that adrenal volumes may increase prior to preterm birth, but studies are limited. This study aimed to: (i) demonstrate reproducibility of magnetic resonance imaging (MRI) derived adrenal volumetry; (ii) derive normal ranges of total adrenal volumes, and adrenal: body volume for normal; (iii) compare with those who have spontaneous very preterm birth; and (iv) correlate with histopathological chorioamnionitis. MATERIAL AND METHODS: Patients at high risk of preterm birth prior to 32 weeks were prospectively recruited, and included if they did deliver prior to 32 weeks; a control group who delivered an uncomplicated pregnancy at term was also recruited. T2 weighted images of the entire uterus were obtained, and a deformable slice-to-volume method was used to reconstruct the fetal abdomen. Adrenal and body volumes were obtained via manual segmentation, and adrenal: body volume ratios generated. Normal ranges were created using control data. Differences between groups were investigated accounting for the effect of gestation by use of regression analysis. Placental histopathology was reviewed for pregnancies delivering preterm. RESULTS: A total of 56 controls and 26 cases were included in the analysis. Volumetry was consistent between observers. Adrenal volumes were not higher in the case group (p = 0.2); adrenal: body volume ratios were higher (p = 0.011), persisting in the presence of chorioamnionitis (p = 0.017). A cluster of three pairs of adrenal glands below the fifth centile were noted among the cases all of whom had a protracted period at risk of preterm birth prior to MRI. CONCLUSIONS: Adrenal: body volume ratios are significantly larger in fetuses who go on to deliver preterm than those delivering at term. Adrenal volumes were not significantly larger, we hypothesize that this could be due to an adrenal atrophy in fetuses with fulminating chorioamnionitis. A straightforward relationship of adrenal size being increased prior to preterm birth should not be assumed.

Reliability and Feasibility of Low-Field-Strength Fetal MRI at 0.55 T during Pregnancy.

Background The benefits of using low-field-strength fetal MRI to evaluate antenatal development include reduced image artifacts, increased comfort, larger bore size, and potentially reduced costs, but studies about fetal low-field-strength MRI are lacking. Purpose To evaluate the reliability and feasibility of low-field-strength fetal MRI to assess anatomic and functional measures in pregnant participants using a commercially available 0.55-T MRI scanner and a comprehensive 20-minute protocol. Materials and Methods This prospective study was performed at a large teaching hospital (St Thomas' Hospital; London, England) from May to November 2022 in healthy pregnant participants and participants with pregnancy-related abnormalities using a commercially available 0.55-T MRI scanner. A 20-minute protocol was acquired including anatomic T2-weighted fast-spin-echo, quantitative T2*, and diffusion sequences. Key measures like biparietal diameter, transcerebellar diameter, lung volume, and cervical length were evaluated by two radiologists and an MRI-experienced obstetrician. Functional organ-specific mean values were given. Comparison was performed with existing published values and higher-field MRI using linear regression, interobserver correlation, and Bland-Altman plots. Results A total of 79 fetal MRI examinations were performed (mean gestational age, 29.4 weeks ± 5.5 [SD] [age range, 17.6-39.3 weeks]; maternal age, 34.4 years ± 5.3 [age range, 18.4-45.5 years]) in 47 healthy pregnant participants (control participants) and in 32 participants with pregnancy-related abnormalities. The key anatomic two-dimensional measures for the 47 healthy participants agreed with large cross-sectional 1.5-T and 3-T control studies. The interobserver correlations for the biparietal diameter in the first 40 consecutive scans were 0.96 (95% CI: 0.7, 0.99; P = .002) for abnormalities and 0.93 (95% CI: 0.86, 0.97; P < .001) for control participants. Functional features, including placental and brain T2* and placental apparent diffusion coefficient values, strongly correlated with gestational age (mean placental T2* in the control participants: 5.2 msec of decay per week; R2 = 0.66; mean T2* at 30 weeks, 176.6 msec; P < .001). Conclusion The 20-minute low-field-strength fetal MRI examination protocol was capable of producing reliable structural and functional measures of the fetus and placenta in pregnancy. Clinical trial registration no. REC 21/LO/0742 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Gowland in this issue.

Antibiotic treatment of bacterial vaginosis to prevent preterm delivery: Systematic review and individual participant data meta-analysis.

BACKGROUND: Bacterial vaginosis (BV) increases preterm delivery (PTD) risk, but treatment trials showed mixed results in preventing PTD. OBJECTIVES: Determine, using individual participant data (IPD), whether BV treatment during pregnancy reduced PTD or prolonged time-to-delivery. DATA SOURCES: Cochrane Systematic Review (2013), MEDLINE, EMBASE, journal searches, and searches (January 2013-September 2022) ("bacterial vaginosis AND pregnancy") of (i) clinicaltrials.gov; (ii) Cochrane Central Register of Controlled Trials; (iii) World Health Organization International Clinical Trials Registry Platform Portal; and (iv) Web of Science ("bacterial vaginosis"). STUDY SELECTION AND DATA EXTRACTION: Studies randomising asymptomatic pregnant individuals with BV to antibiotics or control, measuring delivery gestation. Extraction was from original data files. Bias risk was assessed using the Cochrane tool. Analysis used "one-step" logistic and Cox random effect models, adjusting gestation at randomisation and PTD history; heterogeneity by I2 . Subgroup analysis tested interactions with treatment. In sensitivity analyses, studies not providing IPD were incorporated by "multiple random-donor hot-deck" imputation, using IPD studies as donors. RESULTS: There were 121 references (96 studies) with 23 eligible trials (11,979 participants); 13 studies (6915 participants) provided IPD; 12 (6115) were incorporated. Results from 9 (4887 participants) not providing IPD were imputed. Odds ratios for PTD for metronidazole and clindamycin versus placebo were 1.00 (95% CI 0.84, 1.17), I2  = 62%, and 0.59 (95% CI 0.42, 0.82), I2  = 0 before; and 0.95 (95% CI 0.81, 1.11), I2  = 59%, and 0.90 (95% CI: 0.72, 1.12), I2  = 0, after imputation. Time-to-delivery did not differ from null with either treatment. Including imputed IPD, there was no evidence that either drug was more effective when administered earlier, or among those with a PTD history. CONCLUSIONS: Clindamycin, but not metronidazole, was beneficial in studies providing IPD, but after imputing data from missing IPD studies, treatment of BV during pregnancy did not reduce PTD, nor prolong pregnancy, in any subgroup or when started earlier in gestation.

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.

Scale-up of a novel vital signs alert device to improve maternity care in Sierra Leone: a mixed methods evaluation of adoption.

BACKGROUND: The CRADLE (Community blood pressure monitoring in Rural Africa: Detection of underLying pre-Eclampsia) Vital Signs Alert device-designed specifically to improve maternity care in low resource settings-had varying impact when trialled in different countries. To better understand the contextual factors that may contribute to this variation, this study retrospectively evaluated the adoption of CRADLE, during scale-up in Sierra Leone. METHODS: This was a mixed methods study. A quantitative indicator of adoption (the proportion of facilities trained per district) was calculated from existing training records, then focus groups were held with 'CRADLE Champions' in each district (n = 32), to explore adoption qualitatively. Template Analysis was used to deductively interpret qualitative data, guided by the NASSS (non-adoption, abandonment, scale-up, spread, sustainability) Framework. FINDINGS: Substantial but non-significant variation was found in the proportion of facilities trained in each district (range 59-90%) [X2 (7, N = 8) = 10.419, p = 0.166]. Qualitative data identified complexity in two NASSS domains that may have contributed to this variation: 'the technology' (for example, charging issues, difficulty interpreting device output and concerns about ongoing procurement) and 'the organisation' (for example, logistical barriers to implementing training, infighting and high staff turnover). Key strategies mentioned to mitigate against these issues included: transparent communication at all levels; encouraging localised adaptations during implementation (including the involvement of community leaders); and selecting Champions with strong soft skills (particularly conflict resolution and problem solving). CONCLUSIONS: Complexity related to the technology and the organisational context were found to influence the adoption of CRADLE in Sierra Leone, with substantial inter-district variation. These findings emphasise the importance of gaining an in-depth understanding of the specific system and context in which a new healthcare technology is being implemented. This study has implications for the ongoing scale-up of CRADLE, and for those implementing or evaluating other health technologies in similar contexts.

Many women die during pregnancy and childbirth from causes that could be prevented, and the vast majority of these deaths occur in low-resource settings. The 'CRADLE Vital Signs Alert' is a medical device that helps identify problems during pregnancy­designed specifically for healthcare professionals in low-resource settings. However, for unknown reasons, the device appears to have varying impact according to the country or setting in which it is used. This study aimed to explore in depth whether, and why, healthcare professionals in Sierra Leone adopted the device and engaged in training (or not). Between March 2020 and January 2021, the CRADLE device and training package was disseminated across 8 districts in Sierra Leone. This relied on a few healthcare workers (nominated 'CRADLE Champions') to voluntarily distribute the devices and training in their local areas. Group discussions were held with CRADLE Champions in each district after the rollout to gather their feedback. In addition, the proportion of facilities trained in each district was recorded. The study found differences in how well the device and training was adopted in each district. Common challenges reported across districts related to technological difficulties (such as issues charging the devices) and organisational barriers (such as high levels of staff turnover at facilities). These findings will help to inform future rollout of the CRADLE device and training in Sierra Leone and highlight factors that may need to be considered by those implementing other health technologies in similar settings.

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.

Planned delivery or expectant management in preeclampsia: an individual participant data meta-analysis.

OBJECTIVE: Pregnancy hypertension is a leading cause of maternal and perinatal mortality and morbidity. Between 34+0 and 36+6 weeks gestation, it is uncertain whether planned delivery could reduce maternal complications without serious neonatal consequences. In this individual participant data meta-analysis, we aimed to compare planned delivery to expectant management, focusing specifically on women with preeclampsia. DATA SOURCES: We performed an electronic database search using a prespecified search strategy, including trials published between January 1, 2000 and December 18, 2021. We sought individual participant-level data from all eligible trials. STUDY ELIGIBILITY CRITERIA: We included women with singleton or multifetal pregnancies with preeclampsia from 34 weeks gestation onward. METHODS: The primary maternal outcome was a composite of maternal mortality or morbidity. The primary perinatal outcome was a composite of perinatal mortality or morbidity. We analyzed all the available data for each prespecified outcome on an intention-to-treat basis. For primary individual patient data analyses, we used a 1-stage fixed effects model. RESULTS: We included 1790 participants from 6 trials in our analysis. Planned delivery from 34 weeks gestation onward significantly reduced the risk of maternal morbidity (2.6% vs 4.4%; adjusted risk ratio, 0.59; 95% confidence interval, 0.36-0.98) compared with expectant management. The primary composite perinatal outcome was increased by planned delivery (20.9% vs 17.1%; adjusted risk ratio, 1.22; 95% confidence interval, 1.01-1.47), driven by short-term neonatal respiratory morbidity. However, infants in the expectant management group were more likely to be born small for gestational age (7.8% vs 10.6%; risk ratio, 0.74; 95% confidence interval, 0.55-0.99). CONCLUSION: Planned early delivery in women with late preterm preeclampsia provides clear maternal benefits and may reduce the risk of the infant being born small for gestational age, with a possible increase in short-term neonatal respiratory morbidity. The potential benefits and risks of prolonging a pregnancy complicated by preeclampsia should be discussed with women as part of a shared decision-making process.

The effectiveness of decision aids for pregnancy related decision-making in women with pre-pregnancy morbidity; systematic review and meta-analysis.

INTRODUCTION: Women with pre-existing morbidity arising from medical conditions or previous caesarean section are at higher risk of adverse pregnancy outcomes compared to women without such morbidity. Women often face complex pregnancy-related decision-making that may be characterized by conflicting maternal and perinatal priorities. The aim of this systematic review and meta-analysis was to assess randomised controlled trials of decision aids to evaluate whether they are effective at reducing decisional conflict scores and to evaluate what type of decision aids are most effective for women with pre-existing morbidity in pregnancy. METHODS: We searched Medline (via Ovid), Embase (via Ovid), CINAHL (via EBSCO) from the earliest entries until September 2021. We selected randomised controlled trials comparing patient decision aids for women with pre-existing morbidity with usual clinical practice or a control intervention. Study characteristics and Jadad risk of bias was recorded. Meta-analysis by pre-existing morbidity type was performed using Stata 17 and the data was presented with a Forest Plot. Random effects models were used to calculate summary estimates if there was substantial clinical or statistical heterogeneity and post mean DCS scores were described in a sensitivity analysis and presented as a line graph, to improve clinical interpretation of results.. A narrative synthesis of the selected studies evaluated what type of decision aid works and for in what circumstances. RESULTS: Ten randomised controlled trials, which reported data from 4028 women, were included. Patient decision aids were evaluated in women with pre-existing morbidity who were undertaking pregnancy-related decision-making. Patient decision aids reduced decisional conflict scale scores by an additional - 3.7, 95% Confidence Interval - 5.9% to - 1.6%) compared to the control group. Women with pre-existing medical conditions were more conflicted at baseline and had greater reductions in decisional conflict scale score (mean difference vs. control group: - 6.6%; 95% CI - 9.8% to - 3.3%), in contrast to those with previous caesarean section (mean difference - 2.4%; 95% CI - 4.8% to - 0.1%). There was limited evidence on the effect of decision aids on health outcomes. Decision aids reduced unwanted variation in decision-making support across maternity settings. CONCLUSION: Patient decision aids are effective tools to support personalised care planning and informed decision-making in women with pre-existing morbidity. Women with pre-existing medical morbidity were more conflicted at baseline and were more likely to benefit from decision aids. Adoption of aids in this population may lead to improve adherence and health outcomes, warranting further research.

Postnatal health and care following hypertensive disorders in pregnancy: a prospective cohort study (BPiPP study).

INTRODUCTION: One in 10 women have hypertensive disorders in pregnancy (HDP) and are at risk of adverse short- and long-term health outcomes, yet there is limited information on their postnatal health and care needs. This study aimed to look at postnatal physical and psychological morbidity in women with HDP, compared to women without HDP, and the postnatal care received in both groups. METHODS: Within a prospective cohort study, women with and without HDP were identified and recruited on the postnatal ward of 17 maternity units across England and invited to complete a short baseline questionnaire. At 3 months postpartum, women were sent a follow-up questionnaire, with reminders. The principal outcomes were the mean score at 3 months for the Edinburgh Postnatal Depression Scale (EPDS) and the EuroQol Group 5-dimension (EQ-5D) scale. RESULTS: One thousand eight hundred twenty-nine women agreed to participate. Of these, 1757 (96%) completed the baseline questionnaire: 769 (44%) women had HDP and 988 (56%) women did not. Despite a difference in health-related quality of life and symptoms of depression at baseline between the two groups, at 3 months postnatal, within the 653 women who completed their follow-up questionnaire (37.2% of those who completed the baseline questionnaire) there were no significant differences between the groups (median EQ-5D VAS: 85 in women with HDP, 85 in women without HDP, p = 0.99 and mean EPDS score 5.5 in women with HDP, 5.0 in women without HDP, p = 0.80). Overall levels of physical postnatal morbidity were high, with 89% reporting one or more morbidities. Approximately 9% of women were re-admitted within 3 months after birth, higher in the HDP group (13.1%) higher compared to women without HDP (5.5%; RR 2.41; 95% CI 1.44-4.05). CONCLUSION: Overall levels of physical and psychological morbidity were high in this postnatal population. Although there were increased needs of women with HDP in the immediate postnatal period (compared to other women), their health assessments were similar at 3 months. This study highlights the unmet needs of women in the postnatal period, in addition to a missed opportunity to influence future pregnancies and improve the longer-term health of women and their babies.

Evaluating the use of the QUiPP app and its impact on the management of threatened preterm labour: A cluster randomised trial.

BACKGROUND: Preterm delivery (before 37 weeks of gestation) is the single most important contributor to neonatal death and morbidity, with lifelong repercussions. However, the majority of women who present with preterm labour (PTL) symptoms do not deliver imminently. Accurate prediction of PTL is needed in order ensure correct management of those most at risk of preterm birth (PTB) and to prevent the maternal and fetal risks incurred by unnecessary interventions given to the majority. The QUantitative Innovation in Predicting Preterm birth (QUIPP) app aims to support clinical decision-making about women in threatened preterm labour (TPTL) by combining quantitative fetal fibronectin (qfFN) values, cervical length (CL), and significant PTB risk factors to create an individualised percentage risk of delivery. METHODS AND FINDINGS: EQUIPTT was a multi-centre cluster randomised controlled trial (RCT) involving 13 maternity units in South and Eastern England (United Kingdom) between March 2018 and February 2019. Pregnant women (n = 1,872) between 23+0 and 34+6 weeks' gestation with symptoms of PTL in the analysis period were assigned to either the intervention (762) or control (1,111). The mean age of the study population was 30.2 (+/- SD 5.93). A total of 56.0% were white, 19.6% were black, 14.2% were Asian, and 10.2% were of other ethnicities. The intervention was the use of the QUiPP app with admission, antenatal corticosteroids (ACSs), and transfer advised for women with a QUiPP risk of delivery >5% within 7 days. Control sites continued with their conventional management of TPTL. Unnecessary management for TPTL was a composite primary outcome defined by the sum of unnecessary admission decisions (admitted and delivery interval >7 days or not admitted and delivery interval ≤7 days) and the number of unnecessary in utero transfer (IUT) decisions/actions (IUT that occurred or were attempted >7 days prior to delivery) and ex utero transfers (EUTs) that should have been in utero (attempted and not attempted). Unnecessary management of TPTL was 11.3% (84/741) at the intervention sites versus 11.5% (126/1094) at control sites (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.66-1.42, p = 0.883). Control sites frequently used qfFN and did not follow UK national guidance, which recommends routine treatment below 30 weeks without testing. Unnecessary management largely consisted of unnecessary admissions which were similar at intervention and control sites (10.7% versus 10.8% of all visits). In terms of adverse outcomes for women in TPTL <36 weeks, 4 women from the intervention sites and 12 from the control sites did not receive recommended management. If the QUiPP percentage risk was used as per protocol, unnecessary management would have been 7.4% (43/578) versus 9.9% (134/1,351) (OR 0.72, 95% CI 0.45-1.16). Our external validation of the QUiPP app confirmed that it was highly predictive of delivery in 7 days; receiver operating curve area was 0.90 (95% CI 0.85-0.95) for symptomatic women. Study limitations included a lack of compliance with national guidance at the control sites and difficulties in implementation of the QUiPP app. CONCLUSIONS: This cluster randomised trial did not demonstrate that the use of the QUiPP app reduced unnecessary management of TPTL compared to current management but would safely improve the management recommended by the National Institute for Health and Care Excellence (NICE). Interpretation of qfFN, with or without the QUiPP app, is a safe and accurate method for identifying women most likely to benefit from PTL interventions. TRIAL REGISTRATION: ISRCTN Registry ISRCTN17846337.

The effect of smoking on COVID-19 severity: A systematic review and meta-analysis.

Various comorbidities represent risk factors for severe coronavirus disease 2019 (COVID-19). The impact of smoking on COVID-19 severity has been previously reported in several meta-analyses limited by small sample sizes and poor methodology. We aimed to rigorously and definitively quantify the effects of smoking on COVID-19 severity. MEDLINE, Embase, CENTRAL, and Web of Science were searched between 1 December 2019 and 2 June 2020. Studies reporting smoking status of hospitalized patients with different severities of disease and/or at least one clinical endpoint of interest (disease progression, intensive care unit admission, need for mechanical ventilation, and mortality) were included. Data were pooled using a random-effects model. This study was registered on PROSPERO: CRD42020180920. We analyzed 47 eligible studies reporting on 32 849 hospitalized COVID-19 patients, with 8417 (25.6%) reporting a smoking history, comprising 1501 current smokers, 5676 former smokers, and 1240 unspecified smokers. Current smokers had an increased risk of severe COVID-19 (risk ratios [RR]: 1.80; 95% confidence interval [CI]: 1.14-2.85; P = .012), and severe or critical COVID-19 (RR: 1.98; CI: 1.16-3.38; P = .012). Patients with a smoking history had a significantly increased risk of severe COVID-19 (RR: 1.31; CI: 1.12-1.54; P = .001), severe or critical COVID-19 (RR: 1.35; CI: 1.19-1.53; P < .0001), in-hospital mortality (RR: 1.26; CI: 1.20-1.32; P < .0001), disease progression (RR: 2.18; CI: 1.06-4.49; P = .035), and need for mechanical ventilation (RR: 1.20; CI: 1.01-1.42; P = .043). Patients with any smoking history are vulnerable to severe COVID-19 and worse in-hospital outcomes. In the absence of current targeted therapies, preventative, and supportive strategies to reduce morbidity and mortality in current and former smokers are crucial.

The impact of chronic kidney disease Stages 3-5 on pregnancy outcomes.

BACKGROUND: Contemporaneous data are required for women with chronic kidney disease (CKD) Stages 3-5 to inform pre-pregnancy counselling and institute appropriate antenatal surveillance. METHODS: A retrospective cohort study in women with CKD Stages 3-5 after 20 weeks' gestation was undertaken in six UK tertiary renal centres in the UK between 2003 and 2017. Factors predicting adverse outcomes and the impact of pregnancy in accelerating the need for renal replacement therapy (RRT) were assessed. RESULTS: There were 178 pregnancies in 159 women, including 43 women with renal transplants. The live birth rate was 98%, but 56% of babies were born preterm (before 37 weeks' gestation). Chronic hypertension was the strongest predictor of delivery before 34 weeks' gestation. Of 121 women with known pre-pregnancy hypertension status, the incidence of delivery before 34 weeks was 32% (31/96) in women with confirmed chronic hypertension compared with 0% (0/25) in normotensive women. The risk of delivery before 34 weeks doubled in women with chronic hypertension from 20% [95% confidence interval (CI) 9-36%] to 40% (95% CI 26-56%) if the gestational fall in serum creatinine was <10% of pre-pregnancy concentrations. Women with a urinary protein:creatinine ratio >100 mg/mmol prior to pregnancy or before 20 weeks' gestation had an increased risk for birthweight below the 10th centile (odds ratio 2.57, 95% CI 1.20-5.53). There was a measurable drop in estimated glomerular filtration rate (eGFR) between pre-pregnancy and post-partum values (4.5 mL/min/1.73 m2), which was greater than the annual decline in eGFR prior to pregnancy (1.8 mL/min/1.73 m2/year). The effect of pregnancy was, therefore, equivalent to 1.7, 2.1 and 4.9 years of pre-pregnancy renal disease in CKD Stages 3a, 3b and 4-5, respectively. The pregnancy-associated decline in renal function was greater in women with chronic hypertension and in those with a gestational fall in serum creatinine of <10% of pre-pregnancy concentrations. At 1 year post-partum, 46% (58/126) of women had lost ≥25% of their pre-pregnancy eGFR or required RRT. Most women with renal transplants had CKD Stage 3 and more stable renal function prior to pregnancy. Renal transplantation was not independently associated with adverse obstetric or renal outcomes. CONCLUSIONS: Contemporary pregnancies in women with CKD Stages 3-5 are complicated by preterm delivery, low birthweight and loss of maternal renal function. Chronic hypertension, pre- or early pregnancy proteinuria and a gestational fall in serum creatinine of <10% of pre-pregnancy values are more important predictors of adverse obstetric and renal outcome than CKD Stages 3-5. Pregnancy in women with CKD Stages 3-5 advances the need for dialysis or transplantation by 2.5 years.

Effect of the CRADLE vital signs alert device intervention on referrals for obstetric haemorrhage in low-middle income countries: a secondary analysis of a stepped- wedge cluster-randomised control trial.

BACKGROUND: Obstetric haemorrhage is the leading cause of maternal death worldwide, 99% of which occur in low and middle income countries. The majority of deaths and adverse events are associated with delays in identifying compromise and escalating care. Management of severely compromised pregnant women may require transfer to tertiary centres for specialised treatment, therefore early recognition is vital for efficient management. The CRADLE vital signs alert device accurately measures blood pressure and heart rate, calculates the shock index (heart rate divided by systolic blood pressure) and alerts the user to compromise through a traffic light system reflecting previously validated shock index thresholds. METHODS: This is a planned secondary analysis of data from the CRADLE-3 trial from ten clusters across Africa, India and Haiti where the device and training package were randomly introduced. Referral data were prospectively collected for a 4-week period before, and a 4-week period 3 months after implementation. Referrals from primary or secondary care facilities to higher level care for any cause were recorded. The denominator was the number of women seen for maternity care in these facilities. RESULTS: Between April 1 2016 and Nov 30th, 2017 536,223 women attended maternity care facilities. Overall, 3.7% (n = 2784/74,828) of women seen in peripheral maternity facilities were referred to higher level care in the control period compared to 4.4% (n = 3212/73,371) in the intervention period (OR 0.89; 0.39-2.05) (data for nine sites that were able to collect denominator). Of these 0.29% (n = 212) pre-intervention and 0.16% (n = 120) post-intervention were referred to higher-level facilities for maternal haemorrhage. Although overall referrals did not significantly reduce there was a significant reduction in referrals for obstetric haemorrhage (OR 0.56 (0.39-0.65) following introduction of the device with homogeneity (i-squared 26.1) between sites. There was no increase in any bleeding-related morbidity (maternal death or emergency hysterectomy). CONCLUSIONS: Referrals for obstetric haemorrhage reduced following implementation of the CRADLE Vital Signs Alert Device, occurring without an increase in maternal death or emergency hysterectomy. This demonstrates the potential benefit of shock index in management pathways for obstetric haemorrhage and targeting limited resources in low- middle- income settings. TRIAL REGISTRATION: This study is registered with the ISRCTN registry, number ISRCTN41244132 (02/02/2016).

Antenatal thymus volumes in fetuses that delivered <32 weeks' gestation: An MRI pilot study.

INTRODUCTION: Infection and inflammation have been implicated in the etiology and subsequent morbidity associated with preterm birth. At present, there are no tests to assess for fetal compartment infection. The thymus, a gland integral in the fetal immune system, has been shown to involute in animal models of antenatal infection, but its response in human fetuses has not been studied. This study aims: (a) to generate magnetic resonance imaging (MRI) -derived fetal thymus volumes standardized for fetal weight; (b) to compare standardized thymus volumes from fetuses that delivered before 32 weeks of gestation with fetuses that subsequently deliver at term; (c) to assess thymus size as a predictor of preterm birth; and (d) to correlate the presence of chorioamnionitis and funisitis at delivery with thymic volumes in utero in fetuses that subsequently deliver preterm. MATERIAL AND METHODS: Women at high-risk of preterm birth at 20-32 weeks of gestation were recruited. A control group was obtained from existing data sets acquired as part of three research studies. A fetal MRI was performed on a 1.5T or 3T MRI scanner: T2 weighted images were obtained of the entire uterine content and specifically the fetal thorax. A slice-to-volume registration method was used for reconstruction of three-dimensional images of the thorax. Thymus segmentations were performed manually. Body volumes were calculated by manual segmentation and thymus:body volume ratios were generated. Comparison of groups was performed using multiple regression analysis. Normal ranges were created for thymus volume and thymus:body volume ratios using the control data. Receiver operating curves (ROC) curves were generated for thymus:body volume ratio and gestation-adjusted thymus volume centiles as predictors of preterm birth. Placental histology was analyzed where available from pregnancies that delivered very preterm and the presence of chorioamnionitis/funisitis was noted. RESULTS: Normative ranges were created for thymus volume, and thymus volume was standardized for fetal size from fetuses that subsequently delivered at term, but were imaged at 20-32 weeks of gestation. Image data sets from 16 women that delivered <32 weeks of gestation (ten with ruptured membranes and six with intact membranes) and 80 control women that delivered >37 weeks were included. Mean gestation at MRI of the study group was 28+4  weeks (SD 3.2) and for the control group was 25+5  weeks (SD 2.4). Both absolute fetal thymus volumes and thymus:body volume ratios were smaller in fetuses that delivered preterm (P < .001). Of the 16 fetuses that delivered preterm, 13 had placental histology, 11 had chorioamnionitis, and 9 had funisitis. The strongest predictors of prematurity were the thymus volume Z-score and thymus:body volume ratio Z-score (ROC areas 0.915 and 0.870, respectively). CONCLUSIONS: We have produced MRI-derived normal ranges for fetal thymus and thymus:body volume ratios between 20 and 32 weeks of gestation. Fetuses that deliver very preterm had reduced thymus volumes when standardized for fetal size. A reduced thymus volume was also a predictor of spontaneous preterm delivery. Thymus volume may be a suitable marker of the fetal inflammatory response, although further work is needed to assess this, increasing the sample size to correlate the extent of chorioamnionitis with thymus size.

Midwifery continuity of care versus standard maternity care for women at increased risk of preterm birth: A hybrid implementation-effectiveness, randomised controlled pilot trial in the UK.

BACKGROUND: Midwifery continuity of care is the only health system intervention shown to reduce preterm birth (PTB) and improve perinatal survival, but no trial evidence exists for women with identified risk factors for PTB. We aimed to assess feasibility, fidelity, and clinical outcomes of a model of midwifery continuity of care linked with a specialist obstetric clinic for women considered at increased risk for PTB. METHODS AND FINDINGS: We conducted a hybrid implementation-effectiveness, randomised, controlled, unblinded, parallel-group pilot trial at an inner-city maternity service in London (UK), in which pregnant women identified at increased risk of PTB were randomly assigned (1:1) to either midwifery continuity of antenatal, intrapartum, and postnatal care (Pilot study Of midwifery Practice in Preterm birth Including women's Experiences [POPPIE] group) or standard care group (maternity care by different midwives working in designated clinical areas). Pregnant women attending for antenatal care at less than 24 weeks' gestation were eligible if they fulfilled one or more of the following criteria: previous cervical surgery, cerclage, premature rupture of membranes, PTB, or late miscarriage; previous short cervix or short cervix this pregnancy; or uterine abnormality and/or current smoker of tobacco. Feasibility outcomes included eligibility, recruitment and attrition rates, and fidelity of the model. The primary outcome was a composite of appropriate and timely interventions for the prevention and/or management of preterm labour and birth. We analysed by intention to treat. Between 9 May 2017 and 30 September 2018, 334 women were recruited; 169 women were allocated to the POPPIE group and 165 to the standard group. Mean maternal age was 31 years; 32% of the women were from Black, Asian, and ethnic minority groups; 70% were in employment; and 46% had a university degree. Nearly 70% of women lived in areas of social deprivation. More than a quarter of women had at least one pre-existing medical condition and multiple risk factors for PTB. More than 75% of antenatal and postnatal visits were provided by a named/partner midwife, and a midwife from the POPPIE team was present at 80% of births. The incidence of the primary composite outcome showed no statistically significant difference between groups (POPPIE group 83.3% versus standard group 84.7%; risk ratio 0.98 [95% confidence interval (CI) 0.90 to 1.08]; p = 0.742). Infants in the POPPIE group were significantly more likely to have skin-to-skin contact after birth, to have it for a longer time, and to breastfeed immediately after birth and at hospital discharge. There were no differences in other secondary outcomes. The number of serious adverse events was similar in both groups and unrelated to the intervention (POPPIE group 6 versus standard group 5). Limitations of this study included the limited power and the nonmasking of group allocation; however, study assignment was masked to the statistician and researchers who analysed the data. CONCLUSIONS: In this study, we found that it is feasible to set up and achieve fidelity of a model of midwifery continuity of care linked with specialist obstetric care for women at increased risk of PTB in an inner-city maternity service in London (UK), but there is no impact on most outcomes for this population group. Larger appropriately powered trials are needed, including in other settings, to evaluate the impact of relational continuity and hypothesised mechanisms of effect based on increased trust and engagement, improved care coordination, and earlier referral on disadvantaged communities, including women with complex social factors and social vulnerability. TRIAL REGISTRATION: We prospectively registered the pilot trial on the UK Clinical Research Network Portfolio Database (ID number: 31951, 24 April 2017). We registered the trial on the International Standard Randomised Controlled Trial Number (ISRCTN) (Number: 37733900, 21 August 2017) and before trial recruitment was completed (30 September 2018) when informed that prospective registration for a pilot trial was also required in a primary clinical trial registry recognised by WHO and the International Committee of Medical Journal Editors (ICMJE). The protocol as registered and published has remained unchanged, and the analysis conforms to the original plan.