Metformin use and preeclampsia risk in women with diabetes: a two-country cohort analysis.

BACKGROUND: Metformin is a hypoglycaemic medication that has been proposed to treat or prevent preeclampsia. Combining national birth data from Scotland and Sweden, we investigated whether metformin used during pregnancy was associated with an altered risk of developing a hypertensive disorder of pregnancy. METHODS: We utilised data from two population-based cohorts: Scotland (2012-2018) and Sweden (2007-2019). Nulliparous women with gestational diabetes or type 2 diabetes who had birth outcome data linked with medications prescribed during pregnancy were included. The association between metformin prescription and hypertensive disorders of pregnancy was characterised using inverse probability weighted regression analysis, adjusting for variables that predict metformin use and potential confounders. Adverse neonatal outcomes were included as secondary outcomes. Results from both countries were then combined in a meta-analysis using a random effects model. RESULTS: The Scottish cohort included 3859 women with gestational diabetes or type 2 diabetes. Of these women, 30.8% (n = 1187) received at least one metformin prescription during pregnancy. For Sweden, 7771 women with gestational diabetes were included where 19.3% (1498) used metformin during pregnancy. Metformin prescription was not associated with an altered risk of any hypertensive disorder of pregnancy (Scotland adjusted relative risk (aRR) 0.88 [95% confidence interval (CI) 0.66-1.19]; Sweden aRR 1.08 [95% CI 0.86-1.37]) or preeclampsia (Scotland aRR 1.02 [95% CI 0.66-1.60]; Sweden aRR 1.00 [95% CI 0.72-1.39]). Combining adjusted results in a meta-analysis produced similar findings, with a pooled RR of 0.98 (95% CI 0.79-1.18) for any hypertensive disorder and RR 1.01 ([95% CI 0.73-1.28]) for preeclampsia. For neonatal outcomes, metformin was associated with a reduced risk of birthweight > 4500 g in Scotland (aRR 0.39 [95% CI 0.21-0.71]) but not in Sweden. There was no association between metformin and preterm birth or birthweight < 3rd or < 10th percentiles. Pooling results from both countries, metformin was not associated with adverse neonatal outcomes, including preterm birth (RR 1.00 [95% CI 0.89-1.13]), and birthweight < 10th percentile (RR 0.82 [95% CI 0.60-1.13]) or < 3rd percentile (RR 0.78 [95% CI 0.41-1.48]). CONCLUSIONS: In this two-country analysis, metformin use in pregnancy among women with diabetes was not associated with an altered risk of developing any hypertensive disorder of pregnancy. In the combined meta-analysis, metformin was not associated with an altered risk of adverse neonatal outcomes.

Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial.

INTRODUCTION: Preterm pre-eclampsia is a leading cause of maternal morbidity and mortality. The Pre-eclampsia Intervention 2 (PI 2) trial suggested that metformin sustained release (XR) may prolong gestation by a week in pregnant women undergoing expectant management (7.6 days, geometric mean ratio 1.39, 95% CI 0.99 to 1.95; p=0.057). These findings should be confirmed with a larger sample size, and we need to know if such a prolongation improves neonatal outcome. Here, we describe the protocol for such a follow-up trial. METHODS: The PI 3 trial is a phase III, intention-to-treat, double-blind, placebo-controlled randomised clinical trial to assess if metformin XR can prolong gestation and improve neonatal outcomes in women undergoing expectant management for preterm pre-eclampsia. We will recruit women who are between 26+0 and 31+6 weeks pregnant. Women will be randomised to receive either 3 g metformin XR or an identical placebo in divided daily doses. The primary outcome is prolongation of pregnancy. Secondary outcomes are neonatal birth weight and length of neonatal care admission (an indicator of neonatal health at birth). All other outcomes will be exploratory. We will record tolerability and adverse events. We plan a sample size of 500 participants to be powered for the primary and secondary outcomes. ETHICS AND DISSEMINATION: PI 3 has ethical approval (Health Research Ethics Committee 2, Stellenbosch University, Protocol number M21/03/007, Project ID 21639, Federal Wide Assurance Number 00001372, Institutional Review Board Number IRB0005239), and is registered with the Pan African Clinical Trial Registry (PACTR202104532026017) and the South African Medicine Control Council (20211211). Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: PACTR202104532026017).

Aspirin for preeclampsia prevention in low- and middle-income countries: mind the gaps.

Preeclampsia is a syndrome that continues to be a major contributor to maternal and neonatal mortality, especially in low-income countries. Low-dose aspirin reduces the risk of preeclampsia, but the mechanism is still unknown. Risk factors to identify women at risk of preeclampsia are based on clinical characteristics. Women identified as high-risk would benefit from aspirin treatment initiated, preferably at the end of the first trimester. Current efforts have largely focused on developing screening algorithms that incorporate clinical risk factors, maternal biomarkers, and uterine artery Doppler evaluated in the first trimester. However, most studies on preeclampsia are conducted in high-income settings, raising uncertainties about whether the information gained can be totally applied in low-resource settings. In low- and middle-income countries, lack of adequate antenatal care and late commencement of antenatal care visits pose significant challenges for both screening for preeclampsia and initiating aspirin treatment. Furthermore, the preventive effect of first-trimester screening based on algorithms and subsequent aspirin treatment is primarily seen for preterm preeclampsia, and reviews indicate minimal or no impact on reducing the risk of term preeclampsia. The lack of evidence regarding the effectiveness of aspirin in preventing term preeclampsia is a crucial concern, as 75% of women will develop this subtype of the syndrome. Regarding adverse outcomes, low-dose aspirin has been linked to a possible higher risk of postpartum hemorrhage, a condition as deadly as preeclampsia in many low- and middle-income countries. The increased risk of postpartum hemorrhage among women in low-income settings should be taken into consideration when discussing which pregnant women would benefit from the use of aspirin and the ideal aspirin dosage for preventing preeclampsia. In addition, women's adherence to aspirin during pregnancy is crucial for determining its effectiveness and complications, an aspect often overlooked in trials. In this review, we analyze the knowledge gaps that must be addressed to safely increase low-dose aspirin use in low- and middle-income countries, and we propose directions for future research.

Long-term impact of COVID-19 on nursing and care delivery: A national survey among anaesthetic and critical care nurses.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has put an exceptional strain on intensive care delivery and has significantly impacted nursing practice in the intensive care unit, consequently affecting nurses' working environment and health. Little is known about the long-term impact on the nursing workforce and care delivery in intensive care and anaesthetic departments. AIM/OBJECTIVE: This cross-sectional study aimed to describe the long-term impact of the COVID-19 pandemic on the nursing profession and nursing care from the perspectives of anaesthetic and critical care nurses. METHODS: In this study, an online questionnaire with open- and close-ended questions was distributed to registered nurses working in anaesthesia and intensive care between February 8 and March 7, 2022. The data were analysed using content analysis and descriptive statistics. RESULTS: Of the 514 registered nurses who responded to the questionnaire, 256 (50%) worked in anaesthesia care and 215 (42%) in intensive care. The long-term impact of COVID-19 was expressed in three categories: nursing care on hold, insights and experiences forming a new professional identity, and the impact of organisational conditions on the profession. Critical care nurses considered nursing care comparable to that before the COVID-19 pandemic. Nurse anaesthetics experienced changes in nursing tasks and activities compared to that before the COVID-19 pandemic. CONCLUSIONS: Nursing care is still influenced by the pandemic due to the lack of resources and persistent high workload and needs to be reclaimed and prioritised. Re-establishing high-quality nursing care is a shared responsibility of the organisation and nursing profession, and the organisation needs to create prerequisites for this. Furthermore, nurses' views and insights into their profession developed both positively and negatively during the pandemic, which must be further considered, including the profession's values.

Comparing analog and digital neurocognitive tests with older adults: a study of the ISPOCD battery vs. a digital test battery from Mindmore.

BACKGROUND: Delayed neurocognitive recovery and neurocognitive disorder are common postoperative complications among older adults. The assessment of these complications traditionally relies on analog neurocognitive tests, predominantly using the test battery from the ISPOCD-study as the standard approach. However, analog tests are time-consuming and necessitate trained staff which poses limitations. The potential availability of a digital neurocognitive test as an alternative to the ISPOCD remains unknown. We conducted a comparative study between the analog test battery from ISPOCD and the self-administrated digital test battery developed by Mindmore. METHODS: We conducted a crossover study with 50 cognitively healthy older adults ≥ 60 years of age recruited in Stockholm Sweden, between February and April 2022. The primary outcome focused on measuring comparability between the two test batteries. Our secondary outcomes included assessing participants' perceptions and attitudes about the tests with qualitative interviews and their usability experiences. RESULTS: Fifty older adults, mean age 76, female 56%, with a university or college degree 48% participated in the study. The sub tests in two test batteries demonstrated a medium-large correlation (r = 0.3-0.5), except for one measure. For four out of six measures, significant differences were found with medium to large effect sizes, ranging from 0.57-1.43. Two categories were recognized in the qualitative analysis: self-competing in a safe environment, and experience with technology. Participants expressed feeling safe and at ease during the assessment, with some preferring the digital test over the analog. Participants reported a high level of usability with the digital test and a majority participants (n = 47) reported they would undergo the digital test for a potential future surgery. CONCLUSIONS: The digital test battery developed by Mindmore offers several advantages, including rapid access to test results, easy comprehension, and use for participants, thereby increased accessibility of cognitive screening. TRIAL REGISTRATION NUMBER: NCT05253612; ClinicalTrials.gov, 24/02/2022.

Novel Associations Between Mid-Pregnancy Cardiovascular Biomarkers and Preeclampsia: An Explorative Nested Case-Control Study.

Prediction of women at high risk of preeclampsia is important for prevention and increased surveillance of the disease. Current prediction models need improvement, particularly with regard to late-onset preeclampsia. Preeclampsia shares pathophysiological entities with cardiovascular disease; thus, cardiovascular biomarkers may contribute to improving prediction models. In this nested case-control study, we explored the predictive importance of mid-pregnancy cardiovascular biomarkers for subsequent preeclampsia. We included healthy women with singleton pregnancies who had donated blood in mid-pregnancy (~ 18 weeks' gestation). Cases were women with subsequent preeclampsia (n = 296, 10% of whom had early-onset preeclampsia [< 34 weeks]). Controls were women who had healthy pregnancies (n = 333). We collected data on maternal, pregnancy, and infant characteristics from medical records. We used the Olink cardiovascular II panel immunoassay to measure 92 biomarkers in the mid-pregnancy plasma samples. The Boruta algorithm was used to determine the predictive importance of the investigated biomarkers and first-trimester pregnancy characteristics for the development of preeclampsia. The following biomarkers had confirmed associations with early-onset preeclampsia (in descending order of importance): placental growth factor (PlGF), matrix metalloproteinase (MMP-12), lectin-like oxidized LDL receptor 1, carcinoembryonic antigen-related cell adhesion molecule 8, serine protease 27, pro-interleukin-16, and poly (ADP-ribose) polymerase 1. The biomarkers that were associated with late-onset preeclampsia were BNP, MMP-12, alpha-L-iduronidase (IDUA), PlGF, low-affinity immunoglobulin gamma Fc region receptor II-b, and T cell surface glycoprotein. Our results suggest that MMP-12 is a promising novel preeclampsia biomarker. Moreover, BNP and IDUA may be of value in enhancing prediction of late-onset preeclampsia.

Pregnancy-associated cardiovascular risks and postpartum care; an opportunity for interventions aiming at health preservation and disease prevention.

Cardiovascular disease (CVD) is the leading cause of premature death and disability for female individuals around the world and the rates are increasing in those aged 35-44 years. Certain pregnancy complications (Pregnancy-associated Cardiovascular Risks (P-CVR))are linked to an increased risk of future CVD making pregnancy and the postpartum period as an ideal time to screen individuals for underlying, often unrecognized, cardiovascular risk factors. Pregnancy complications associated with an increased risk of future CVD including the hypertensive disorders of pregnancy, gestational diabetes, idiopathic preterm birth, delivery of a growth restricted baby and a placental abruption that leads to delivery. A number of guidelines and research groups recommend postpartum CVR screening, counseling and lifestyle intervention for all those who have had one or more of P-CVRs starting within the first six months postpartum. An individualized plan for postpartum screening should be created with the individual and lifestyle interventions discussed.

Can single-cell and spatial omics unravel the pathophysiology of pre-eclampsia?

Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Characterised by the onset of hypertension and proteinuria in the second half of pregnancy, it can lead to maternal end-organ injury such as cerebral ischemia and oedema, pulmonary oedema and renal failure, and potentially fatal outcomes for both mother and fetus. The causes of the different maternal end-organ phenotypes of pre-eclampsia and why some women develop pre-eclampsia condition early in pregnancy have yet to be elucidated. Omics methods include proteomics, genomics, metabolomics, transcriptomics. These omics techniques, previously mostly used on bulk tissue and individually, are increasingly available at a single cellular level and can be combined with each other. Multi-omics techniques on a single-cell or spatial level provide us with a powerful tool to understand the pathophysiology of pre-eclampsia. This review will explore the status of omics methods and how they can and could contribute to understanding the pathophysiology of pre-eclampsia.

Usability and feasibility of a digital cognitive screening tool measuring older adults' early postoperative neurocognitive recovery: a protocol for a pilot study.

INTRODUCTION: Delayed neurocognitive recovery, also identified as early postoperative cognitive decline (POCD), is a common complication after surgery, with advanced age being the most important risk factor. As the geriatric population is increasing worldwide, and number of older adults undergoing surgery continues to rise, so will the incidence of POCD. Only a small proportion use digital cognitive tests for measuring postoperative neurocognitive performance compared with analogue tests. This study aims to evaluate a digital cognitive screening tool, Mindmore Postoperative version (Mindmore-P), in a perioperative setting to determine its feasibility and usability, and to compare preoperative cognition with early postoperative neurocognitive performance. Further, to determine associations between neurocognitive performance and perioperative factors as well as to explore patients' experiences of early neurocognitive recovery. METHODS AND ANALYSIS: We will include 50 patients (aged ≥60 years) undergoing elective abdominal surgery under general anaesthesia. Cognitive functions will be measured with Mindmore-P preoperatively and on postoperative day (POD) 1 or 2 as well as 2-3 weeks after surgery. Preoperatively, frailty, (Clinical Frailty Scale), depression (Geriatric Depression Scale-15), functional status (12-item WHO Disability Assessment Schedule 2.0) and pre-recovery status (Swedish web version Quality of Recovery Scale, SwQoR) will be measured. Delirium will be assessed by Nu-DESC (Nursing Delirium Screening Scale) twice a day, with start on POD 1 and until the patient is discharged from the hospital. Outcomes at 2-3 weeks postoperatively are postoperative recovery (SwQoR), depression, functional status and usability (System Usability Scale) of Mindmore-P. Postoperative recovery will also be measured POD 1 or 2. We will also explore feasibility and experience of early postoperative neurocognitive recovery with interviews approximately 1 month after surgery. ETHICS AND DISSEMINATION: This study is approved by the Swedish Ethical Review Authority (REC Reference: 2022-03593-01) and will follow the principles outlined in the 1964 Helsinki Declaration and its later amendments. Results from this study will be disseminated in peer-reviewed journals, scientific conferences and in social media. TRIAL REGISTRATION NUMBER: NCT05564195.