Lived experience of hypertensive disorders of pregnancy: a systematic review and meta-synthesis.

BACKGROUND: Hypertensive disorders are major causes of maternal and neonatal morbidity and mortality, affecting ∼10% pregnancies worldwide. OBJECTIVE: Understanding the lived experience of women with hypertensive disorders during pregnancy is important to inform best practice and provide holistic care. STUDY DESIGN: This is a systematic review and meta-synthesis of studies containing qualitative components relating to direct lived experience of hypertensive disorders of pregnancy. Medline via Ovid, Embase via Ovid, CINAHL via Ebsco, PsycINFO via Ebsco, Scopus, Web of Science Core Collection, and ASSIA via ProQuest were searched between database inception and June 2024. Quality assessment was performed using the Critical Appraisal Skills Programme checklist for qualitative research. Themes were labeled and organized into a framework using NVivo software. RESULTS: Eighteen studies were included in the meta-synthesis. Anxiety, stress, fear and panic emerged as the most common emotional experiences during hypertensive disorders of pregnancy. Loss of control was also mentioned frequently and consistently across studies (frequency effect size 38.9% and intensity effect size 15.3%). Emotional responses to physical symptoms or lack thereof, and feelings about the impact of the complicated pregnancy on family and community also emerged as central themes associated with hypertensive disorders of pregnancy. CONCLUSION: A range of emotional experiences was captured across the studies included in our meta-synthesis, some of which were observed across global settings whereas others were context-dependent. Interventions and care pathways for pregnancies affected by hypertensive disorders should aim to support women through complex emotional experiences as well as reducing morbidity and mortality.

Implementation challenges in preeclampsia care: perspectives from health care professionals in urban Uganda.

BACKGROUND: Sub-Saharan Africa bears the burden of 70% of maternal deaths worldwide, of which ∼10% are attributable to hypertensive disorders of pregnancy, primarily complications of preeclampsia. In other global settings, outcomes of pregnancies affected by preeclampsia are improved with timely and effective medical care. OBJECTIVE: This study aimed to explore the perspectives of local health care professionals on how preeclampsia care is currently delivered in the study setting and what challenges they experience in providing prompt and safe care. We identified specific objectives of exploring stakeholder perceptions of (1) recognizing preeclampsia and (2) timely intervention when preeclampsia is diagnosed. We also explored the wider system factors (eg, cultural, financial, and logistic challenges) that health care professionals perceived as affecting their ability to deliver optimal preeclampsia care. STUDY DESIGN: Individual semistructured interviews were conducted with health care professionals and stakeholders. The findings were analyzed using thematic analysis. RESULTS: Thirty-three participants contributed to the study, including doctors and midwives with varying degrees of clinical experience and external stakeholders. The following 5 key themes emerged: delayed patient presentation, recognizing the unwell patient with preeclampsia, the challenges of the existing triage system, stakeholder disconnect, and ways of learning from each other. Health care professionals referenced an important psychosocial perspective associated with preeclampsia in the study setting, which may influence the likelihood of seeking care through traditional healers rather than hospital-based routes. CONCLUSION: We identify the key barriers to improving maternal and neonatal outcomes of preeclampsia, described at both the institutional level and within the wider setting. The study provides invaluable contextual information that suggests that a systems-based approach to health care quality improvement may be effective in reducing rates of maternal and neonatal morbidity and mortality.

Association between maternal hemoglobin concentration and educational attainment in mid-childhood in a high-resource obstetric setting: a prospective cohort study.

BACKGROUND: Although maternal hemoglobin levels during pregnancy are commonly associated with perinatal outcomes, their link to childhood neurodevelopment remains uncertain. OBJECTIVE: This study aimed to examine the associations between maternal hemoglobin in early and late pregnancy and the educational attainment of offspring mid-childhood in a high-resource obstetric setting. STUDY DESIGN: Pregnancy data from a prospective birth cohort (Pregnancy Outcome Prediction Study, Cambridge, United Kingdom, 2008-2012, N=3285) were linked to mid-childhood educational outcomes (Department for Education, United Kingdom). Regression models adjusted for maternal, child, and socioeconomic factors were used to determine associations between maternal hemoglobin, pregnancy complications, and offspring educational outcomes (aged 5-7 years). RESULTS: No association was observed between maternal hemoglobin at 12 weeks and the likelihood of either adverse pregnancy outcomes or children meeting expected educational standards between ages 5-7 years. Higher maternal hemoglobin at 28 weeks was associated with an increased risk of small-for-gestational-age infants (adjusted odds ratio, 1.26 [95% confidence interval, 1.11-1.59]; P=.002) and preterm birth (adjusted odds ratio, 1.38 [95% confidence interval, 1.11-1.81]; P=.005). There were no adverse birth outcomes associated with anemia. However, children of mothers who were anemic at 28 weeks had ∼40% increased risk of not attaining expected educational standards at age 5 (adjusted odds ratio, 1.42 [95% confidence interval, 1.03-1.95]; P=.03). There was no association between maternal anemia at 28 weeks and educational performance at ages 6-7. No associations were found between high maternal hemoglobin concentrations (top decile) or change in hemoglobin concentrations between 12 and 28 weeks and childhood educational attainment. CONCLUSION: Maternal anemia at 28 weeks of pregnancy is associated with reduced educational attainment at 5 years old but not at older ages (6-7 years old). A proactive approach to increasing maternal hemoglobin in high-resource settings is unlikely to impact long-term childhood educational attainment.

Maternal high body mass index, but not gestational diabetes, is associated with poorer educational attainment in mid-childhood.

BACKGROUND: Previous studies suggest that gestational diabetes mellitus is associated with poorer cognitive outcomes in children. However, confounding factors, especially maternal body mass index, have been poorly accounted for. OBJECTIVE: This study aimed to examine the independent associations between maternal body mass index, gestational diabetes mellitus status, and educational outcomes. STUDY DESIGN: Antenatal data from a prospective birth cohort (Pregnancy Outcome Prediction Study, 2008-2012, Cambridge, United Kingdom) were linked to mid-childhood educational outcomes (Department for Education, United Kingdom). A total of 3249 children born at term were stratified by maternal gestational diabetes mellitus status and body mass index at booking (<25 vs ≥25 kg/m2). Regression models adjusted for relevant maternal, child, and socioeconomic factors were used to determine associations with academic outcomes at ages of 5 to 7 years. RESULTS: No differences in educational attainment were found between children exposed to gestational diabetes mellitus and nonexposed children. Neither maternal glucose levels measured at 11 to 14 or 24 to 28 weeks, nor acceleration of the fetal abdominal circumference growth velocity were related to educational attainment at ages of 5 to 7 years. Children of mothers with booking body mass index ≥25 kg/m2 (vs <25 kg/m2) were ∼50% more likely to not meet expected educational standards regardless of gestational diabetes mellitus status (age 5: adjusted odds ratio, 1.44; 95% confidence interval, 1.19-1.74; P<.001; age 6: adjusted odds ratio, 1.61; 95% confidence interval, 1.28-2.02; P<.001). The association between maternal body mass index and offspring educational attainment is dose-dependent and robust to stratification by gestational diabetes mellitus status and adjustment for socioeconomic factors. CONCLUSION: Mid-childhood educational attainment is not associated with maternal glucose status. This may provide important reassurance for pregnant women and clinicians. However, maternal body mass index is associated with lower childhood educational attainment and may be modifiable with intervention before or during pregnancy.

Precision gestational diabetes treatment: a systematic review and meta-analyses.

BACKGROUND: Gestational Diabetes Mellitus (GDM) affects approximately 1 in 7 pregnancies globally. It is associated with short- and long-term risks for both mother and baby. Therefore, optimizing treatment to effectively treat the condition has wide-ranging beneficial effects. However, despite the known heterogeneity in GDM, treatment guidelines and approaches are generally standardized. We hypothesized that a precision medicine approach could be a tool for risk-stratification of women to streamline successful GDM management. With the relatively short timeframe available to treat GDM, commencing effective therapy earlier, with more rapid normalization of hyperglycaemia, could have benefits for both mother and fetus. METHODS: We conducted two systematic reviews, to identify precision markers that may predict effective lifestyle and pharmacological interventions. RESULTS: There was a paucity of studies examining precision lifestyle-based interventions for GDM highlighting the pressing need for further research in this area. We found a number of precision markers identified from routine clinical measures that may enable earlier identification of those requiring escalation of pharmacological therapy (to metformin, sulphonylureas or insulin). This included previous history of GDM, Body Mass Index and blood glucose concentrations at diagnosis. CONCLUSIONS: Clinical measurements at diagnosis could potentially be used as precision markers in the treatment of GDM. Whether there are other sensitive markers that could be identified using more complex individual-level data, such as omics, and if these can feasibly be implemented in clinical practice remains unknown. These will be important to consider in future studies.

Gestational diabetes (GDM) is high blood sugar first detected during pregnancy. Normalizing blood sugar levels quickly is important to avoid pregnancy complications. Many women achieve this with lifestyle changes, such as to diet, but some need to inject insulin or take tablets. We did two thorough reviews of existing research to see if we could predict which women need medication. Firstly we looked for ways to identify the characteristics of women who benefit most from changing their lifestyles to treat GDM, but found very limited research on this topic. We secondly searched for characteristics that help identify women who need medication to treat GDM. We found some useful characteristics that are obtained during routine pregnancy care. Further studies are needed to test if additional information could provide even better information about how we could make GDM treatment more tailored for individuals during pregnancy.

The metabolic response of human trophoblasts derived from term placentas to metformin.

AIMS/HYPOTHESIS: Metformin is increasingly used therapeutically during pregnancy worldwide, particularly in the treatment of gestational diabetes, which affects a substantial proportion of pregnant women globally. However, the impact on placental metabolism remains unclear. In view of the association between metformin use in pregnancy and decreased birthweight, it is essential to understand how metformin modulates the bioenergetic and anabolic functions of the placenta. METHODS: A cohort of 55 placentas delivered by elective Caesarean section at term was collected from consenting participants. Trophoblasts were isolated from the placental samples and treated in vitro with clinically relevant doses of metformin (0.01 mmol/l or 0.1 mmol/l) or vehicle. Respiratory function was assayed using high-resolution respirometry to measure oxygen concentration and calculated [Formula: see text]. Glycolytic rate and glycolytic stress assays were performed using Agilent Seahorse XF assays. Fatty acid uptake and oxidation measurements were conducted using radioisotope-labelled assays. Lipidomic analysis was conducted using LC-MS. Gene expression and protein analysis were performed using RT-PCR and western blotting, respectively. RESULTS: Complex I-supported oxidative phosphorylation was lower in metformin-treated trophoblasts (0.01 mmol/l metformin, 61.7% of control, p<0.05; 0.1 mmol/l metformin, 43.1% of control, p<0.001). The proton efflux rate arising from glycolysis under physiological conditions was increased following metformin treatment, up to 23±5% above control conditions following treatment with 0.1 mmol/l metformin (p<0.01). There was a significant increase in triglyceride concentrations in trophoblasts treated with 0.1 mmol/l metformin (p<0.05), particularly those of esters of long-chain polyunsaturated fatty acids. Fatty acid oxidation was reduced by ~50% in trophoblasts treated with 0.1 mmol/l metformin compared with controls (p<0.001), with no difference in uptake between treatment groups. CONCLUSIONS/INTERPRETATION: In primary trophoblasts derived from term placentas metformin treatment caused a reduction in oxidative phosphorylation through partial inactivation of complex I and potentially by other mechanisms. Metformin-treated trophoblasts accumulate lipids, particularly long- and very-long-chain polyunsaturated fatty acids. Our findings raise clinically important questions about the balance of risk of metformin use during pregnancy, particularly in situations where the benefits are not clear-cut and alternative therapies are available.

The Uterine Environment and Childhood Obesity Risk: Mechanisms and Predictions.

PURPOSE OF REVIEW: Childhood obesity is a growing health problem in many populations, hence the urgent need to unravel the underlying mechanisms. Some evidence suggests that exposure to suboptimal intrauterine environments can program foetal metabolic health, with adverse consequences in later life, including susceptibility to childhood obesity. FINDINGS: Factors such as high and low foetal birth weight, excessive gestational-weight-gain, maternal stress and smoking are all associated with increased risk of childhood obesity in observational studies. Animal models, where both genetic background and the postnatal environment can be carefully controlled, suggest that several different mechanisms, including epigenetic changes, dysregulation of adipose tissue development and programming of appetite, may be key drivers of developmental programming of childhood obesity. However, the influence of genetics and the post-natal environment are much more difficult to disentangle as independent effects in human studies, which are also complicated by low follow-up rates. Suboptimal intrauterine environments interact with maternal and foetal genetics and with the postnatal environment to contribute to the risk of childhood obesity. Maternal metabolic challenges, for example obesity and insulin resistance, contribute to the risk of foetal overgrowth and subsequent adiposity in childhood. To protect the long-term health of populations, research focusing on effective means of identifying and intervening in the transgenerational cycle of childhood obesity is required.

Barriers to progress in pregnancy research: How can we break through?

Healthy pregnancies are fundamental to healthy populations, but very few therapies to improve pregnancy outcomes are available. Fundamental concepts-for example, placentation or the mechanisms that control the onset of labor-remain understudied and incompletely understood. A key issue is that research efforts must capture the complexity of the tripartite maternal-placental-fetal system, the dynamics of which change throughout gestation. Studying pregnancy disorders is complicated by the difficulty of creating maternal-placental-fetal interfaces in vitro and the uncertain relevance of animal models to human pregnancy. However, newer approaches include trophoblast organoids to model the developing placenta and integrated data-science approaches to study longer-term outcomes. These approaches provide insights into the physiology of healthy pregnancy, which is the first step to identifying therapeutic targets in pregnancy disorders.

Perinatal outcomes in pregnancies complicated by maternal cardiomyopathy: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to systematically assess perinatal outcomes of pregnancies complicated by maternal cardiomyopathy. DATA SOURCES: PubMed, Ovid Embase, Ovid MEDLINE, the Cochrane Library, and ClinicalTrials.gov were systematically searched from inception to August 25, 2022. STUDY ELIGIBILITY CRITERIA: Observational cohort, case-control, and case-cohort studies in human populations were included if they reported predefined perinatal outcomes in pregnant women with cardiomyopathy (any subtype) and an appropriate control population (either pregnant women with no known cardiac disease or pregnant women with noncardiomyopathy cardiac disease). METHODS: Of note, 2 reviewers independently assessed the articles for eligibility and risk of bias, and conflicts were resolved by a third reviewer. Data were extracted and synthesized according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis of Observational Studies in Epidemiology guidelines. RESULTS: Here, 13 studies (representing 2,291,024 pregnancies) were eligible for inclusion. Perinatal death was more likely in neonates born to women with cardiomyopathy than in (1) neonates born to women with no cardiac disease (stillbirth: odds ratio, 20.82; 95% confidence interval, 6.68-64.95; I2 = not available; P<.00001; neonatal mortality: odds ratio, 6.75; 95% confidence interval, 3.54-12.89; I2=0%; P<.00001) and (2) neonates born to women with other forms of cardiac disease (stillbirth: odds ratio, 3.75; 95% confidence interval, 1.86-7.59; I2=0%; P=.0002; neonatal mortality: odds ratio, 2.42; 95% confidence interval, 1.39-4.21; I2=0%; P=.002). Pregnancies affected by maternal cardiomyopathy were significantly more likely to result in preterm birth (odds ratio, 2.21; 95% confidence interval, 1.31-3.73; I2=77%; P=.003) and small-for-gestational-age neonates (odds ratio, 2.97; 95% confidence interval, 2.38-3.70; I2=47%; P<.00001), both major causes of short- and long-term morbidities, than pregnancies affected by other forms of cardiac disease. CONCLUSION: There was an increased likelihood of adverse perinatal outcomes in pregnancies affected by maternal cardiomyopathy compared with both pregnancies affected by noncardiomyopathy cardiac disease and pregnancies without cardiac disease. Women with cardiomyopathy who plan to get pregnant should receive detailed counseling regarding these risks and have their pregnancies managed by experienced multidisciplinary teams that can provide close fetal monitoring and neonatology expertise.

Maternal left ventricular function and adverse neonatal outcomes in women with cardiac disease.

PURPOSE: To evaluate the relationship between maternal left ventricular systolic function, utero-placental circulation, and risk of adverse neonatal outcomes in women with cardiac disease. METHODS: 119 women managed in the pregnancy heart clinic (2019-2021) were identified. Women were classified by their primary cardiac condition. Adverse neonatal outcomes were: low birth weight (< 2500 g), small-for-gestational-age (< 10th birth-weight centile), pre-term delivery (< 37 weeks' gestation), and fetal demise (> 20 weeks' gestation). Parameters of left ventricular systolic function (global longitudinal strain, radial strain, ejection fraction, average S', and cardiac output) were calculated and pulsatility index was recorded from last growth scan. RESULTS: Adverse neonatal outcomes occurred in 28 neonates (24%); most frequently in valvular heart disease (n = 8) and cardiomyopathy (n = 7). Small-for-gestational-age neonates were most common in women with cardiomyopathy (p = 0.016). Early pregnancy average S' (p = 0.03), late pregnancy average S' (p = 0.02), and late pregnancy cardiac output (p = 0.008) were significantly lower in women with adverse neonatal outcomes than in those with healthy neonates. There was a significant association between neonatal birth-weight centile and global longitudinal strain (p = 0.04) and cardiac output (p = 0.0002) in late pregnancy. Pulsatility index was highest in women with cardiomyopathy (p = 0.007), and correlated with average S' (p < 0.0001) and global longitudinal strain (p = 0.03) in late pregnancy. CONCLUSION: Women with cardiac disease may not tolerate cardiovascular adaptations required during pregnancy to support fetal growth. Adverse neonatal outcomes were associated with reduced left ventricular systolic function and higher pulsatility index. The association between impaired systolic function and reduced fetal growth is supported by insufficient utero-placental circulation.

Why mothers die at a busy tertiary urban hospital in Kampala, Uganda: a comprehensive review of maternal deaths 2016-2018 and implications for quality improvement to reduce deaths.

Background: Reviewing maternal deaths and drawing out lessons for clinical practice is part of an effective cohesive intervention strategy to reduce future deaths. Objective: To review maternal deaths at the National Referral hospital in Kampala over a 3-year period (2016-2018) to determine causes of death, extent of preventability, proportion of deaths notified and audited as per national guidelines. Methods: Trained-multidisciplinary panels (obstetricians and senior midwives) conducted retrospective reviews of maternal deaths that occurred. Results: Major causes of deaths: obstetric haemorrhage (158/350; 45%), hypertensive disorders of pregnancy (87/350; 25%) and infection (95/350; 27%). Overall, 294/350 (84%) of maternal deaths were considered preventable. In 95% (332/350) of cases, delays within healthcare facilities were identified (64%; 226/350). We note that only 115/350 (33%) cases had been audited. This proportion did not change during the studied period. In 48% (167/350) of cases, notification to the Ministry of Health occurred, but only 11% of deaths (39/350) were notified within the recommended 24-hours. Conclusions: A high proportion (84%) of deaths were preventable. Significant delays to care occurred within health-care facilities. Results suggest that a well-supported, and timely maternal death review process with targeted and pragmatic interventions might be effective in reducing maternal deaths in this setting.

Learning from maternal deaths due to uterine rupture: review of cases from peri-urban Uganda.

BACKGROUND: Maternal deaths from uterine rupture continue to occur globally, with particularly high rates in sub-Saharan Africa. Maternal death reviews have been shown to be an effective part of cohesive strategies to prevent future deaths. OBJECTIVE: This study aimed to conduct maternal death reviews for all deaths following uterine rupture in the study center, to assess preventability, and to synthesize key learning points that may help to prevent future maternal deaths following uterine rupture. STUDY DESIGN: Thorough case reviews of all maternal deaths from 2016 to 2018 at the study center (a national referral hospital in urban Uganda) were conducted by trained multidisciplinary panels of obstetricians and midwives. Medical records of women who died following uterine rupture (n=37, 10.6% of all maternal deaths) were extracted for further analysis. RESULTS: Most maternal deaths due to uterine rupture (36/37, 97%) were preventable, with most having been still potentially preventable after the women reached the study center (24/36, 67%). Obstructed labor was the leading cause of uterine rupture, accounting for 73% (27/37) of cases. Previous cesarean delivery was confirmed in 38% (14/37) of cases. The incidence of grand multiparity was 11% (4/37), and 11% (4/37) were primiparous. Most women (28/37, 76%) died within 24 hours of admission. On arrival at the study center, 19 (51%) were critically ill. Exploratory laparotomy was performed in 54% (20/37) of cases, and a further 35% (13/37) died while awaiting laparotomy. Four women died shortly after arrival at the study center (within 1 hour) and received basic resuscitative treatment; 27% (10/37) of women who died had received antenatal planning or preparation. CONCLUSION: Most deaths due to uterine rupture were preventable. The key lessons that emerged from the reviews were: (1) careful birth preparation and complication awareness for women with known risk factors, (2) early recognition of obstructed labor, (3) close monitoring of obstetrical interventions known to be associated with uterine rupture, and (4) treating incipient or suspected uterine rupture as a time-critical obstetrical emergency. The recommendations emerging from our narrative reviews are suitable for implementation in low-resource obstetrical settings, where high numbers of deaths involving uterine rupture occur.

Sex-specific effects of maternal metformin intervention during glucose-intolerant obese pregnancy on body composition and metabolic health in aged mouse offspring.

AIMS/HYPOTHESIS: Metformin is increasingly used to treat gestational diabetes (GDM) and pregnancies complicated by pregestational type 2 diabetes or polycystic ovary syndrome but data regarding long-term offspring outcome are lacking in both human studies and animal models. Using a mouse model, this study investigated the effects of maternal metformin intervention during obese glucose-intolerant pregnancy on adiposity, hepatic steatosis and markers of metabolic health of male and female offspring up to the age of 12 months. METHODS: C57BL/6J female mice were weaned onto either a control diet (Con) or, to induce pre-conception obesity, an obesogenic diet (Ob). The respective diets were maintained throughout pregnancy and lactation. These obese dams were then randomised to the untreated group or to receive 300 mg/kg oral metformin hydrochloride treatment (Ob-Met) daily during pregnancy. In male and female offspring, body weights and body composition were measured from 1 month until 12 months of age, when serum and tissues were collected for investigation of adipocyte cellularity (histology), adipose tissue inflammation (histology and quantitative RT-PCR), and hepatic steatosis and fibrosis (histochemistry and modified Folch assay). RESULTS: At 12 months of age, male Ob and Ob-Met offspring showed increased adiposity, adipocyte hypertrophy, elevated expression of proinflammatory genes, hyperleptinaemia and hepatic lipid accumulation compared with Con offspring. Male Ob-Met offspring failed to show hyperplasia between 8 weeks and 12 months, indicative of restricted adipose tissue expansion, resulting in increased immune cell infiltration and ectopic lipid deposition. Female Ob offspring were relatively protected from these phenotypes but Ob-Met female offspring showed increased adiposity, adipose tissue inflammation, hepatic lipid accumulation, hyperleptinaemia and hyperinsulinaemia compared with Con female offspring. CONCLUSIONS/INTERPRETATION: Maternal metformin treatment of obese dams increased offspring metabolic risk factors in a sex- and age-dependent manner. These observations highlight the importance of following up offspring of both sexes beyond early adulthood after interventions during pregnancy. Our findings illustrate the complexity of balancing short-term benefits to mother and child vs any potential long-term metabolic effects on the offspring when prescribing therapeutic agents that cross the placenta.

Impact of Metformin Treatment on Human Placental Energy Production and Oxidative Stress.

Metformin is increasingly prescribed in pregnancy, with beneficial maternal effects. However, it is not known how metformin-treatment impacts metabolism and energy production in the developing feto-placental unit. We assessed the human placental response to metformin using both in vivo and in vitro treated samples. trophoblasts were derived from placentas collected from non-laboured Caesarean deliveries at term, then treated in vitro with metformin (0.01 mM, 0.1 mM or vehicle). Metformin-concentrations were measured using liquid-chromatography mass-spectrometry. Oxygen consumption in cultured-trophoblasts was measured using a Seahorse-XF Mito Stress Test. Markers of oxidative-stress were assayed using qRT-PCR. Metformin-transporter mRNA and protein-levels were determined by quantitative RT-PCR and Western-blotting respectively. Metformin concentrations were also measured in sample trios (maternal plasma/fetal plasma/placental tissue) from pregnancies exposed to metformin on clinical-grounds. Maternal and fetal metformin concentrations in vivo were highly correlated over a range of concentrations (R2 = 0.76, p < 0.001; average fetal:maternal ratio 1.5; range 0.8-2.1). Basal respiration in trophoblasts was reduced by metformin treatment (0.01 mM metformin; p < 0.05, 0.1 mM metformin; p < 0.001). Mitochondrial-dependent ATP production and proton leak were reduced after treatment with metformin (p < 0.001). Oxidative stress markers were significantly reduced in primary-trophoblast-cultures following treatment with metformin. There is a close linear relationship between placental, fetal, and maternal metformin concentrations. Primary-trophoblast cultures exposed to clinically-relevant metformin concentrations have reduced mitochondrial-respiration, mitochondrial-dependent ATP-production, and reduced markers of oxidative-stress. Given the crucial role of placental energy-production in supporting fetal growth and well-being during pregnancy, the implications of these findings are concerning for intrauterine fetal growth and longer-term metabolic programming in metformin-exposed pregnancies.

Maternal pregnancy outcomes in women with cardiomyopathy: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to systematically assess the impact of cardiomyopathy on maternal pregnancy outcomes. DATA SOURCES: PubMed, Ovid Embase, Ovid MEDLINE, Cochrane Library, and ClinicalTrials.gov were systematically searched from inception to April 24, 2022. STUDY ELIGIBILITY CRITERIA: Observational cohort, case-control, and case-cohort studies in human populations were included if they reported predefined maternal outcomes for pregnant women with cardiomyopathy (any subtype) and for an appropriate control population (pregnant women with no known heart disease or pregnant women with noncardiomyopathy heart disease). METHODS: Two reviewers independently assessed the articles for eligibility and risk of bias, and conflicts were resolved by a third reviewer. Data were extracted and synthesized according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analyses of Observational Studies in Epidemiology guidelines. RESULTS: A total of 14 studies (n=57,539,306 pregnancies) were eligible for inclusion. Women with cardiomyopathy were more likely to deliver by cesarean delivery than women with no heart disease (odds ratio, 2.96; 95% confidence interval, 2.47-3.55; I2=95%; P≤.00001) or women with noncardiomyopathy heart disease (odds ratio, 1.90; 95% confidence interval, 1.62-2.22; I2=91%; P<.00001). Having cardiomyopathy conferred a greater risk for experiencing severe maternal adverse cardiovascular events during pregnancy when compared with not having any heart disease (odds ratio, 206.64; 95% confidence interval, 192.09-222.28; I2=73%; P<.0001) or having noncardiomyopathy heart disease (odds ratio, 7.09; 95% confidence interval; 6.08-8.27; I2=88%; P<.00001). In-hospital mortality was significantly higher among women with cardiomyopathy than among women with no heart disease (odds ratio, 126.67; 95% confidence interval, 43.01-373.07; I2=87%; P<.00001) or among women with noncardiomyopathy heart disease (odds ratio, 4.30; 95% confidence interval, 3.42-5.40; I2=0%; P<.00001). CONCLUSION: Pregnant women with cardiomyopathy have increased risks for adverse maternal outcomes, including maternal death, when compared with both women with no heart disease and women with noncardiomyopathy heart disease. Our results highlight the importance of preconception risk assessments to allow for informed decision-making before pregnancy. Pregnancies affected by cardiomyopathy are high risk and should be managed by expert, multidisciplinary obstetrical and cardiology teams.

Glucose and oxygen in the early intrauterine environment and their role in developmental abnormalities.

The early life environment can have profound impacts on the developing conceptus in terms of both growth and morphogenesis. These impacts can manifest in a variety of ways, including congenital fetal anomalies, placental dysfunction with subsequent effects on fetal growth, and adverse perinatal outcomes, or via effects on long-term health outcomes that may not be detected until later childhood or adulthood. Two key examples of environmental influences on early development are explored: maternal hyperglycaemia and gestational hypoxia. These are increasingly common pregnancy exposures worldwide, with potentially profound impacts on population health. We explore what is known regarding the mechanisms by which these environmental exposures can impact early intrauterine development and thus result in adverse outcomes in the immediate, short, and long term.

"Post-GDM support would be really good for mothers": A qualitative interview study exploring how to support a healthy diet and physical activity after gestational diabetes.

BACKGROUND: Women with a history of gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes mellitus (T2DM). They are therefore recommended to follow a healthy diet and be physically active in order to reduce that risk. However, achieving and maintaining these behaviours in the postpartum period is challenging. This study sought to explore women's views on suggested practical approaches to achieve and maintain a healthy diet and physical activity to reduce T2DM risk. METHODS: Semi-structured interviews with 20 participants in Cambridgeshire, UK were conducted at three to 48 months after GDM. The participants' current diet and physical activity, intentions for any changes, and views on potential interventions to help manage T2DM risk through these behaviours were discussed. Framework analysis was used to analyse the transcripts. The interview schedule, suggested interventions, and thematic framework were based on a recent systematic review. RESULTS: Most of the participants wanted to eat more healthily and be more active. A third of the participants considered that postpartum support for these behaviours would be transformative, a third thought it would be beneficial, and a third did not want additional support. The majority agreed that more information about the impact of diet and physical activity on diabetes risk, support to exercise with others, and advice about eating healthily, exercising with a busy schedule, monitoring progress and sustaining changes would facilitate a healthy diet and physical activity. Four other suggested interventions received mixed responses. It would be acceptable for this support to be delivered throughout pregnancy and postpartum through a range of formats. Clinicians were seen to have important roles in giving or signposting to support. CONCLUSIONS: Many women would appreciate more support to reduce their T2DM risk after GDM and believe that a variety of interventions to integrate changes into their daily lives would help them to sustain healthier lifestyles.

Maternal but not fetoplacental health can be improved by metformin in a murine diet-induced model of maternal obesity and glucose intolerance.

Maternal obesity is a global problem that increases the risk of short- and long-term adverse outcomes for mother and child, many of which are linked to gestational diabetes mellitus. Effective treatments are essential to prevent the transmission of poor metabolic health from mother to child. Metformin is an effective glucose lowering drug commonly used to treat gestational diabetes mellitus; however, its wider effects on maternal and fetal health are poorly explored. In this study we used a mouse (C57Bl6/J) model of diet-induced (high sugar/high fat) maternal obesity to explore the impact of metformin on maternal and feto-placental health. Metformin (300 mg kg-1  day-1 ) was given to obese females via the diet and was shown to achieve clinically relevant concentrations in maternal serum (1669 ± 568 nM in late pregnancy). Obese dams developed glucose intolerance during pregnancy and had reduced uterine artery compliance. Metformin treatment of obese dams improved maternal glucose tolerance, reduced maternal fat mass and restored uterine artery function. Placental efficiency was reduced in obese dams, with increased calcification and reduced labyrinthine area. Consequently, fetuses from obese dams weighed less (P < 0.001) at the end of gestation. Despite normalisation of maternal parameters, metformin did not correct placental structure or fetal growth restriction. Metformin levels were substantial in the placenta and fetal circulation (109.7 ± 125.4 nmol g-1 in the placenta and 2063 ± 2327 nM in fetal plasma). These findings reveal the distinct effects of metformin administration during pregnancy on mother and fetus and highlight the complex balance of risk vs. benefits that are weighed in obstetric medical treatments. KEY POINTS: Maternal obesity and gestational diabetes mellitus have detrimental short- and long-term effects for mother and child. Metformin is commonly used to treat gestational diabetes mellitus in many populations worldwide but the effects on fetus and placenta are unknown. In a mouse model of diet-induced obesity and glucose intolerance in pregnancy we show reduced uterine artery compliance, placental structural changes and reduced fetal growth. Metformin treatment improved maternal metabolic health and uterine artery compliance but did not rescue obesity-induced changes in the fetus or placenta. Metformin crossed the placenta into the fetal circulation and entered fetal tissue. Metformin has beneficial effects on maternal health beyond glycaemic control. However, despite improvements in maternal physiology, metformin did not prevent fetal growth restriction or placental ageing. The high uptake of metformin into the placental and fetal circulation highlights the potential for direct immediate effects of metformin on the fetus with possible long-term consequences postnatally.