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.

Repeat Placental Growth Factor-Based Testing in Women With Suspected Preterm Preeclampsia: A Stratified Analysis of the PARROT-2 Trial.

BACKGROUND: PlGF (placental growth factor)-based testing reduces severe maternal adverse outcomes. Repeat PlGF-based testing is not associated with improved perinatal or maternal outcomes. This planned secondary analysis aimed to determine whether there is a subgroup of women who benefit from repeat testing. METHODS: Pregnant individuals with suspected preterm preeclampsia were randomized to repeat revealed PlGF-based testing, compared with usual care where testing was concealed. Perinatal and maternal outcomes were stratified by trial group, by initial PlGF-based test result, and by PlGF-based test type (PlGF or sFlt-1 [soluble fms-like tyrosine kinase-1]/PlGF ratio). RESULTS: A total of 1252 pregnant individuals were included. Abnormal initial PlGF-based test identified a more severe phenotype of preeclampsia, at increased risk of adverse maternal and perinatal outcomes. Repeat testing was not significantly associated with clinical benefit in women with abnormal initial results. Of women with a normal initial result, 20% developed preeclampsia, with the majority at least 3 to 4 weeks after initial presentation. Repeat test results were more likely to change from normal to abnormal in symptomatic women (112/415; 27%) compared with asymptomatic women (163/890; 18%). A higher proportion of symptomatic women who changed from normal to abnormal were diagnosed with preeclampsia, compared with asymptomatic women. CONCLUSIONS: Our results do not demonstrate evidence of the clinical benefit of repeating PlGF-based testing if the initial result is abnormal. Judicious use of repeat PlGF-based testing to stratify risk may be considered at least 2 weeks after a normal initial test result, particularly in women who have symptoms or signs of preeclampsia. REGISTRATION: URL: XXX; Unique identifier: ISRCTN85912420.

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.

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.

Perturbation of placental protein glycosylation by endoplasmic reticulum stress promotes maladaptation of maternal hepatic glucose metabolism.

Placental hormones orchestrate maternal metabolic adaptations to support pregnancy. We hypothesized that placental ER stress, which characterizes early-onset pre-eclampsia (ePE), compromises glycosylation, reducing hormone bioactivity and these maladaptations predispose the mother to metabolic disease in later life. We demonstrate ER stress reduces the complexity and sialylation of trophoblast protein N-glycosylation, while aberrant glycosylation of vascular endothelial growth factor reduced its bioactivity. ER stress alters the expression of 66 of the 146 genes annotated with "protein glycosylation" and reduces the expression of sialyltransferases. Using mouse placental explants, we show ER stress promotes the secretion of mis-glycosylated glycoproteins. Pregnant mice carrying placentas with junctional zone-specific ER stress have reduced blood glucose, anomalous hepatic glucose metabolism, increased cellular stress and elevated DNA methyltransferase 3A. Using pregnancy-specific glycoproteins as a readout, we also demonstrate aberrant glycosylation of placental proteins in women with ePE, thus providing a mechanistic link between ePE and subsequent maternal metabolic disorders.

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.

Prevention of gestational diabetes in pregnant women with obesity: protocol for a pilot randomised controlled trial.

BACKGROUND: Obesity in pregnancy increases the risk of gestational diabetes mellitus (GDM) and associated adverse outcomes. Despite metabolic differences, all pregnant women with obesity are considered to have the same risk of developing GDM. Improved risk stratification is required to enable targeted intervention in women with obesity who would benefit the most. The aim of this study is to identify pregnant women with obesity at higher risk of developing GDM and, in a pilot randomised controlled trial (RCT), test feasibility and assess the efficacy of a lifestyle intervention and/or metformin to improve glycaemic control. METHODS: Women aged 18 years or older with a singleton pregnancy and body mass index (BMI) ≥ 30kg/m2 will be recruited from one maternity unit in London, UK. The risk of GDM will be assessed using a multivariable GDM prediction model combining maternal age, mid-arm circumference, systolic blood pressure, glucose, triglycerides and HbA1c. Women identified at a higher risk of developing GDM will be randomly allocated to one of two intervention groups (lifestyle advice with or without metformin) or standard antenatal care. The primary feasibility outcomes are study recruitment, retention rate and intervention adherence and to collect information needed for the sample size calculation for the definitive trial. A process evaluation will assess the acceptability of study processes and procedures to women. Secondary patient-centred outcomes include a reduction in mean glucose/24h of 0.5mmol/l as assessed by continuous glucose monitoring and changes in a targeted maternal metabolome, dietary intake and physical activity. A sample of 60 high-risk women is required. DISCUSSION: Early risk stratification of GDM in pregnant women with obesity and targeted intervention using lifestyle advice with or without metformin could improve glucose tolerance compared to standard antenatal care. The results from this feasibility study will inform a larger adequately powered RCT should the intervention show trends for potential effectiveness. TRIAL REGISTRATION: This study has been approved by the NHS Research Ethics Committee (UK IRAS integrated research application system; reference 18/LO/1500). EudraCT number 2018-000003-16 .

Rule-in and rule-out of pre-eclampsia using DELFIA Xpress PlGF 1-2-3 and sFlt-1: PlGF ratio.

OBJECTIVES: The objective of this study was to explore and validate thresholds for Placental growth factor (PlGF) and soluble fms-like tyrosine-kinase 1 (s-Flt-1) (as s-Flt-1: PlGF ratio), to rule-in and rule-out disease in women with suspected pre-eclampsia, using DELFIA® Xpress PlGF1-2-3 and sFlt-1 assays. STUDY DESIGN: 369 samples from women with suspected or confirmed pre-eclampsia were analysed from a prospective cohort study. MAIN OUTCOME MEASURES: Serum PlGF and sFlt-1: PlGF were quantified using DELFIA® Xpress PlGF1-2-3 and DELFIA® Xpress sFlt-1 tests. Performances were evaluated at established and exploratory thresholds. Low PlGF concentration and sFlt-1: PlGF AUROC were compared. RESULTS: PlGF 1-2-3 concentration thresholds were confirmed to have high performance for rule-in (<50 pg/ml) and rule-out (≥150 pg/ml) pre-eclampsia within seven days (20-33+6 Weeks <50 pg/ml: Negative predictive value (NPV) 90.7% (95% CI 83.9, 95.3); ≥150 pg/ml: NPV 94.8% (95% CI 88.4, 98.3)) and 28 days (20-33+6 Weeks <50 pg/ml: Negative predictive value (NPV) 83.9% (95% CI 76.0, 90.0); ≥150 pg/ml: NPV 92.8% (95% CI 85.7, 97.0)). Optimal sFlt-1: PlGF thresholds for rule-in were ≥ 70 before 34 weeks and ≥ 90 after 34 weeks, and <50 to rule-out pre-eclampsia. Low PlGF alone had comparable performance to sFlt-1: PlGF, but test performance for both was reduced in women with Kidney Disease. CONCLUSIONS: DELFIA® Xpress PlGF1-2-3 and sFlt-1 assays for pre-eclampsia rule-in and rule-out have comparable performance to other established assays, and could be an alternative for clinical use. Performance was not enhanced by use of sFlt-1: PlGF ratio, suggesting that PlGF alone could provide a cheaper alternative to dual biomarker testing.

Multicenter Cohort Study, With a Nested Randomized Comparison, to Examine the Cardiovascular Impact of Preterm Preeclampsia.

[Figure: see text].

A prognostic model to guide decision-making on timing of delivery in late preterm pre-eclampsia: the PEACOCK prospective cohort study.

BACKGROUND: Pre-eclampsia affects around 2-3% of all pregnancies, and is associated with potential serious complications for the woman and the baby. Once diagnosed, progression of the syndrome can be unpredictable, and decisions around timing of delivery need to take into account evolving maternal complications and perinatal morbidity. Novel prognostic models and blood biomarkers for determination of need for delivery in pregnancies with pre-eclampsia are now emerging. OBJECTIVE: The objective of the study was to establish a prognostic model to inform optimal timing of delivery in women with late preterm pre-eclampsia (34+ 0 to 36+ 6 weeks' gestation), comparing novel candidate biomarkers (e.g. placental growth factor) with clinical and routinely collected blood/urinary parameters [incorporated into the PREP-S (Prediction models for Risk of Early-onset Pre-eclampsia - Survival) model] to determine clinically indicated need for delivery for pre-eclampsia (or related complications) within 7 days of assessment. METHODS: Prospective recruitment of women in whom blood samples for placental growth factor and soluble fms-like tyrosine kinase-1 testing was obtained, alongside clinical data, for use within the PREP-S model. Candidate variables were compared using standard methods (sensitivity, specificity, receiver operator curve areas). Estimated probability of early delivery from PREP-S was compared with actual event rates by calibration. SETTING: The PEACOCK (Prognostic indicators of severe disEAse in women with late preterm pre-eClampsia tO guide deCision maKing on timing of delivery) study was a prospective cohort study, nested within the PHOENIX (Pre-eclampsia in HOspital: Early iNductIon or eXpectant management) trial. PARTICIPANTS: Women between 34+ 0 and 36+ 6 weeks' gestation, with a diagnosis of pre-eclampsia, in whom a plasma (ethylenediaminetetraacetic acid) blood sample for placental growth factor testing was obtained, alongside clinical data for the assessment of variables in a prognostic model. MAIN OUTCOME MEASURES: Clinically indicated need for delivery for pre-eclampsia within 7 days of assessment. Statistical analysis: both PREP-S and placental growth factor were assessed and compared using standard methods (sensitivity and specificity for placental growth factor thresholds of 100 pg/ml and < 12 pg/ml, and receiver operating characteristic areas for continuous measurements). The estimated probability of early delivery from PREP-S was compared with actual event rates for women with similar probabilities by calibration. Calibration using logistic regression was also used. RESULTS: Between 27 April 2016 and 24 December 2018, 501 women were recruited to the study. Although placental growth factor testing had high sensitivity (97.9%) for delivery within 7 days, the negative predictive value was only 71.4% and the specificity was low (8.4%). The area under the curve for the clinical prediction model (PREP-S) and placental growth factor in this cohort in determining need for delivery within 7 days was 0.64 (standard error 0.03) and 0.60 (standard error 0.03), respectively, and 0.65 (standard error 0.03) in combination. LIMITATIONS: A high proportion of women in this cohort already had low placental growth factor concentrations at the time of confirmed diagnosis, which reduced the ability of the biomarker to further predict adverse outcomes. CONCLUSIONS: In this group of women with late preterm pre-eclampsia, placental growth factor measurement is not likely to add to the current clinical assessment to help plan care for late preterm pre-eclampsia regarding timing of delivery. Existing models developed in women with early-onset pre-eclampsia to predict complications cannot be used to predict clinically indicated need for delivery in women with late preterm pre-eclampsia. FUTURE WORK: Further statistical modelling and subgroup analysis is being considered to assess if improved model performance in the whole cohort or a subgroup can be achieved. Addition of other biomarkers to the model may also be of use and will be explored. TRIAL REGISTRATION: Current Controlled Trials ISRCTN01879376. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 30. See the NIHR Journals Library website for further project information.

WHY DID WE DO THIS STUDY?: Pre-eclampsia is a condition occurring in pregnancy. The condition can affect the health of the woman and the baby, often affecting the woman's kidneys and liver and the baby's growth. In severe cases, babies can be stillborn. Once pre-eclampsia is diagnosed, the only cure is to deliver the baby. It is often not possible to identify women and babies at high risk of the severe complications of pre-eclampsia who would benefit from early delivery. We wanted to see if we could improve the way that women with pre-eclampsia are assessed to work out who needs to be delivered early to prevent complications. WHAT DID WE DO?: A total of 501 women affected by pre-eclampsia took part in our study and we measured substances in their blood. We used these results, along with other clinical measures, to see if we could improve the way that we try and tell which women need delivery soon. WHAT DID WE FIND?: The blood markers were not able to tell us which women needed delivery within 7 days, and they were not able to improve our detection rate of women who need delivery to prevent complications. WHAT DOES THIS MEAN FOR WOMEN WITH PRE-ECLAMPSIA?: These methods cannot be recommended to plan care for women and babies affected by pre-eclampsia between 34 and 37 weeks' gestation to help tell us when the baby should be born. We need to find better tests to help find out which women and babies are most at risk of the complications of pre-eclampsia.

Prognostic indicators of severe disease in late preterm pre-eclampsia to guide decision making on timing of delivery: The PEACOCK study.

OBJECTIVE: To assess the diagnostic performance of angiogenic biomarkers in determining need for delivery in seven days in women with late preterm preeclampsia. STUDY DESIGN: In a prospective observational cohort study in 36 maternity units across England and Wales, we studied the diagnostic accuracy of placental growth factor (PlGF) and sFlt-1 in determining the risk of complications requiring delivery in late preterm (34+0 to 36+6 weeks' gestation) preeclampsia. Angiogenic biomarkers were measured using the Quidel (PlGF) and Roche (sFlt-1:PlGF ratio) assays. Additional clinical data was obtained for use within the established 'Prediction of complications in early-onset pre-eclampsia' (PREP)-S prognostic model. Biomarkers were assessed using standard methods (sensitivity, specificity, Receiver Operator Curve areas). Estimated probability of early delivery from PREP-S was compared to actual event rates. MAIN OUTCOME MEASURES: Clinically indicated need for delivery for pre-eclampsia within seven days. RESULTS: PlGF (Quidel) testing had high sensitivity (97.9%) for delivery within seven days, but negative predictive value was only 71.4%, with low specificity (8.4%), with similar results from sFlt-1/PlGF assay. The area under the curve for PlGF was 0.60 (SE 0.03), and 0.65 (0.03), and 0.64 (0.03) for PREP-S in combination with PlGF, and sFlt-1:PlGF, respectively. CONCLUSIONS: Angiogenic biomarkers do not add to clinical assessment to help determine need for delivery for women with late preterm pre-eclampsia. Existing models developed in women with early-onset pre-eclampsia to predict complications cannot be used to predict clinically indicated need for delivery in women with late preterm pre-eclampsia.

Iodine status of pregnant women with obesity from inner city populations in the United Kingdom.

BACKGROUND/OBJECTIVES: Iodine is essential for foetal neurodevelopment and growth. Requirements increase in pregnancy to support increased thyroid hormone synthesis for maternal and foetal requirements, and for foetal transfer. Iodine deficiency in pregnancy is widely reported, and obesity has been associated with sub-optimal thyroid function. We evaluated iodine status and its relation with birthweight in a secondary analysis of pregnant women with obesity from multi-ethnic inner-city settings who participated in the UK Pregnancies Better Eating and Activity trial (UPBEAT). SUBJECTS/METHODS: Iodine and creatinine concentrations were evaluated in spot urine samples in the second (15+0-18+6 weeks, n = 954) trimester of pregnancy. We assessed iodine status as urinary iodine concentration (UIC) and urinary iodine-to-creatinine ratio (UI/Cr) and applied WHO/UNICEF/IGN population threshold of median UIC > 150 µg/L for iodine sufficiency. Relationships between iodine status and birthweight were determined using linear and logistic regression with appropriate adjustment, including for maternal BMI and gestational age. RESULTS: Median (IQR) UIC and UI/Cr in the second trimester of pregnancy were 147 µg/L (99-257) and 97 µg/g (59-165), respectively. An UI/Cr <150 µg/g was observed in 70% of women. Compared to women with UI/Cr >150 µg/g, there was a trend for women with UI/Cr <150 µg/g to deliver infants with a lower birthweight (ß = -60.0 g; 95% CI -120.9 to -1.01, P = 0.05). CONCLUSIONS: Iodine status of pregnant women with obesity from this cohort of UK women was suboptimal. Lower iodine status was associated with lower birthweight.

Cohort profile: the eLIXIR Partnership-a maternity-child data linkage for life course research in South London, UK.

PURPOSE: Linked maternity, neonatal and maternal mental health records were created to support research into the early life origins of physical and mental health, in mothers and children. The Early Life Cross Linkage in Research (eLIXIR) Partnership was developed in 2018, generating a repository of real-time, pseudonymised, structured data derived from the electronic health record systems of two acute and one Mental Health Care National Health Service (NHS) Provider in South London. We present early descriptive data for the linkage database and the robust data security and governance structures, and describe the intended expansion of the database from its original development. Additionally, we report details of the accompanying eLIXIR Research Tissue Bank of maternal and neonatal blood samples. PARTICIPANTS: Descriptive data were generated from the eLIXIR database from 1 October 2018 to 30 June 2019. Over 17 000 electronic patient records were included. FINDINGS TO DATE: 10 207 women accessed antenatal care from the 2 NHS maternity services, with 8405 deliveries (8772 infants). This diverse, inner-city maternity service population was born in over 170 countries with an ethnic profile of 46.1% white, 19.1% black, 7.0% Asian, 4.1% mixed and 4.1% other. Of the 10 207 women, 11.6% had a clinical record in mental health services with 3.0% being treated during their pregnancy. This first data extract included 947 infants treated in the neonatal intensive care unit, of whom 19.1% were postnatal transfers from external healthcare providers. FUTURE PLANS: Electronic health records provide potentially transformative information for life course research, integrating physical and mental health disorders and outcomes in routine clinical care. The eLIXIR database will grow by ~14 000 new maternity cases annually, in addition to providing child follow-up data. Additional datasets will supplement the current linkage from other local and national resources, including primary care and hospital inpatient data for mothers and their children.

Rule-in thresholds for DELFIA Xpress PlGF 1-2-3 test for suspected pre-eclampsia.

We aimed to establish a rule-in threshold for the DELFIA Xpress placental growth factor (PlGF) 1-2-3 test. Plasma EDTA samples from 305 women presenting with suspected pre-eclampsia before 35 weeks' gestation were analysed using three different PlGF-based tests: PlGF 1-2-3 test (Perkin Elmer); Triage PlGF test (Quidel); Elecsys immunoassay sFlt-1/PlGF ratio (Roche). The rule-in threshold for PlGF 1-2-3 test created with equivalent specificity of the Quidel and Roche tests was 50 pg/ml. This can be used as a rule-in test for diagnosis of preterm pre-eclampsiarequiring delivery within 14 days (specificity 95.0% (95% CI 91.7-97.2%), positive predictive value50 (95% CI 30.6-69.4%), positive likelihood ratio 10.7 (5.8-20).

Diagnostic accuracy of repeat placental growth factor measurements in women with suspected preeclampsia: A case series study.

INTRODUCTION: Preeclampsia affects about 3% of singleton pregnancies and is characterized by placental dysfunction. It is associated with significant maternal and perinatal morbidity and mortality. The diagnosis of preeclampsia remains a challenge, and the clinical course can develop for weeks before a diagnosis is confirmed. National guidelines have approved placental growth factor (PlGF) testing to rule out suspected preeclampsia, but the utility of repeated PlGF measurement is unknown. The aim of this case series analysis was to evaluate the test performance of repeated PlGF sampling in women presenting with suspected preeclampsia, and to describe relevant clinical outcomes. MATERIAL AND METHODS: Women who presented to maternity services with suspected preeclampsia between 20+0 and 36+6  weeks' gestation who underwent repeat PlGF sampling with a minimum test interval of 7 days were assessed. The outcomes were delivery for preeclampsia within 14 days of sampling, the proportion changing PlGF categories, and time to delivery. RESULTS: In total, 289 women with suspected preeclampsia undergoing repeat PlGF sampling were included. PlGF <100 pg/mL had a high sensitivity (87.5%, 95% confidence interval [CI] 67.6%-97.3%) and a negative predictive value (97.7%, 95% CI 93.5%-99.5%) at the initial test (receiver operating characteristic [ROC] area 0.79, 95% CI 0.68-0.89). Similar test performance was seen for PlGF <100 pg/mL when undertaken as a repeat test (sensitivity 90.7%, 95% CI 85.2%-95.9%, negative predictive value 92.2%, 95% CI 85.3-96.6%). Overall, 25.6% of women changed PlGF category between the first and second PlGF tests. For each PlGF category, determination of time to delivery was similar for first and second tests. CONCLUSIONS: Repeat PlGF measurement demonstrates high negative predictive value for determining preeclampsia requiring delivery in 14 days. Repeat testing may be clinically useful to risk stratify women with ongoing symptoms of disease. Confirmation of the impact of these findings is required in further studies.

Markers of maternal cardiac dysfunction in pre-eclampsia and superimposed pre-eclampsia.

AUTHORS: Frances Conti-Ramsden MBBS Academic Clinical Fellow1, Carolyn Gill PhD BRC Research Assistant1, Paul T Seed MSc CStat Senior Lecturer in Medical Statistics1, Kate Bramham PhD Clinical Senior Lecturer in Nephrology2, Lucy C Chappell PhD NIHR Research Professor in Obstetrics1, Fergus P McCarthy PhD Clinical Senior Lecturer in Obstetrics and Gynaecology1,3. OBJECTIVES: To determine whether glycogen phosphorylase isoenzyme B (GPBB) and/or brain natriuretic peptide (BNP) concentrations are elevated in pre-eclampsia and superimposed pre-eclampsia (SPE), demonstrating cardiac ischaemia and strain. STUDY DESIGN: A nested case-control study was performed using samples and clinical data available from a prospective pregnancy cohort. Four groups were selected: healthy pregnant controls (n = 21), pre-eclampsia (n = 19), pre-existing chronic hypertension (CHT) and/or chronic kidney disease (CKD) without (n = 20) or with superimposed pre-eclampsia (SPE) (n = 19). Plasma samples were taken at time of disease or the third trimester in controls. MAIN OUTCOME MEASURES: Plasma concentrations of GPBB and BNP. RESULTS: There was no significant difference in GPBB plasma concentrations between controls and pre-eclampsia (geometric mean (GM) [95% CI]: 4.74 [2.54-8.84]ng/mL vs 5.01 [2.58-9.74]ng/mL, p = 0.90)), or between CHT and/or CKD and SPE (GM [95% CI]: 9.49 [4.93-18.25]ng/mL vs 10.24 [5.27-19.92]ng/mL, p = 0.87). BNP plasma concentrations were significantly raised in women with pre-eclampsia compared to controls (GM [95% CI]: 31.83 [20.18-50.22]pg/mL vs 11.33 [7.34-17.51]pg/mL, p = 0.001). Women with CKD, but not CHT, who developed SPE had elevated BNP concentrations. There were no significant differences in BNP concentration between women with comorbidity (CHT and/or CKD) and controls. CONCLUSIONS: GPBB has a limited role as a biomarker in hypertensive disorders of pregnancy. BNP concentrations were elevated in pre-eclampsia compared to controls. This suggests cardiac strain at the time of pre-eclampsia. Further studies are needed to examine whether BNP can identify women at increased risk of cardiovascular disease.

Gestational diabetes modifies the association between PlGF in early pregnancy and preeclampsia in women with obesity.

OBJECTIVE: To identify clinical and biomarker risk factors for preeclampsia in women with obesity and to explore interactions with gestational diabetes, a condition associated with preeclampsia. STUDY DESIGN: In women with obesity (body mass index ≥ 30 kg/m2) from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), we examined 8 clinical factors (socio-demographic characteristics, BMI, waist circumference and clinical variables) and 7 biomarkers (HDL cholesterol, hemoglobin A1c, adiponectin, interleukin-6, high sensitivity C-reactive protein, and placental growth factor (PlGF)) in the early second trimester for association with later development of preeclampsia using logistic regression. Factors were selected based on prior association with preeclampsia. Interaction with gestational diabetes was assessed. MAIN OUTCOME MEASURE: Preeclampsia. RESULTS: Prevalence of preeclampsia was 7.3% (59/824). Factors independently associated with preeclampsia were higher mean arterial blood pressure (Odds Ratio (OR) 2.22; 95% Confidence Interval (CI) 1.58-3.12, per 10 mmHg) and lower PlGF (OR 1.39; 95% CI 1.03-1.87, per each lower 1 log2). The association of PlGF with preeclampsia was present amongst obese women without gestational diabetes (OR 1.91; 95% CI 1.32-2.78), but not in those with GDM (OR 1.05; 95% CI 0.67-1.63), p = 0.04 for interaction. CONCLUSION: The relationship between PlGF and preeclampsia differed in women with obesity according to gestational diabetes status, which may suggest different mechanistic pathways to preeclampsia. Whilst replication is required in other populations, this study suggests that performance of prediction models for preeclampsia should be confirmed in pre-specified subgroups.

Relationships between Maternal Obesity and Maternal and Neonatal Iron Status.

: Obesity in pregnancy may negatively influence maternal and infant iron status. The aim of this study was to examine the association of obesity with inflammatory and iron status in both mother and infant in two prospective studies in pregnancy: UPBEAT and SCOPE. Maternal blood samples from obese (n = 245, BMI ≥ 30 kg/m²) and normal weight (n = 245, BMI < 25 kg/m²) age matched pregnant women collected at approximately 15 weeks' gestation, and umbilical cord blood samples collected at delivery, were analysed for a range of inflammatory and iron status biomarkers. Concentrations of C- reactive protein and Interleukin-6 in obese women compared to normal weight women were indicative of an inflammatory response. Soluble transferrin receptor (sTfR) concentration [18.37 nmol/L (SD 5.65) vs 13.15 nmol/L (SD 2.33)] and the ratio of sTfR and serum ferritin [1.03 (SD 0.56) vs 0.69 (SD 0.23)] were significantly higher in obese women compared to normal weight women (P < 0.001). Women from ethnic minority groups (n = 64) had higher sTfR concentration compared with white women. There was no difference in maternal hepcidin between obese and normal weight women. Iron status determined by cord ferritin was not statistically different in neonates born to obese women compared with neonates born to normal weight women when adjusted for potential confounding variables. Obesity is negatively associated with markers of maternal iron status, with ethnic minority women having poorer iron statuses than white women.

Placental lipid droplet composition: Effect of a lifestyle intervention (UPBEAT) in obese pregnant women.

Maternal obesity is associated with adverse outcomes. Placental lipid droplets (LD) have been implicated in maternal-fetal lipid transfer but it is not known whether placental LD fat composition is modifiable. We evaluated the effects of a diet and physical activity intervention in obese pregnant women compared to routine antenatal care (UPBEAT study) on placental LD composition. LD were isolated by ultracentrifugation. Total FAs and phospholipids (phosphatidylcholines, PCs; sphingomyelins, SMs and lyso-phosphatidylcholines, Lyso-PCs) were analyzed by LC-MS/MS. Placenta MFSD2a expression was assessed by western blot. Placental LDs from obese women were comprised of predominantly saturated and monounsaturated FAs. TG and Chol composition was similar between intervention (n = 20) and control (n = 23) groups. PCs containing dihomo-ɣ-linolenic acid in LD were positively associated with gestational weight gain (P < 0.007), and lowered by the intervention. In the whole sample, PCs carrying DHA and arachidonic acid were inversely associated with placental weight. Placenta MFSD2a expression was associated with DHA cord blood metabolites and relationships were observed between LD lipids, especially DHA carrying species, and cord blood metabolites. We describe placenta LD composition for the first time and demonstrate modest, potentially beneficial effects of a lifestyle intervention on LD FAs in obese pregnant women.

Chronic hypertension in pregnancy: impact of ethnicity and superimposed preeclampsia on placental, endothelial, and renal biomarkers.

Black ethnicity is associated with worse pregnancy outcomes in women with chronic hypertension. Preexisting endothelial and renal dysfunction and poor placentation may contribute, but pathophysiological mechanisms underpinning increased risk are poorly understood. This cohort study aimed to investigate the relationship between ethnicity, superimposed preeclampsia, and longitudinal changes in markers of endothelial, renal, and placental dysfunction in women with chronic hypertension. Plasma concentrations of placental growth factor (PlGF), syndecan-1, renin, and aldosterone and urinary angiotensinogen-to-creatinine ratio (AGTCR), protein-to-creatinine ratio (PCR), and albumin-to-creatinine ratio (ACR) were quantified during pregnancy and postpartum in women with chronic hypertension. Comparisons of longitudinal biomarker concentrations were made using log-transformation and random effects logistic regression allowing for gestation. Of 117 women, superimposed preeclampsia was diagnosed in 21% ( n = 25), with 24% ( n = 6) having an additional diagnosis of diabetes. The cohort included 63 (54%) women who self-identified as being of black ethnicity. PlGF concentrations were 67% lower [95% confidence interval (CI) -79 to -48%] and AGTCR, PCR, and ACR were higher over gestation, in women with subsequent superimposed preeclampsia (compared with those without superimposed preeclampsia). PlGF <100 pg/ml at 20-23.9 wk of gestation predicted subsequent birth weight <3rd percentile with 88% sensitivity (95% CI 47-100%) and 83% specificity (95% CI 70-92%). Black women had 43% lower renin (95% CI -58 to -23%) and 41% lower aldosterone (95%CI -45 to -15%) concentrations over gestation. Changes in placental (PlGF) and renal (AGTCR/PCR/ACR) biomarkers predated adverse pregnancy outcome. Ethnic variation in the renin-angiotensin-aldosterone system exists in women with chronic hypertension in pregnancy and may be important in treatment selection.