Association between HbA1c Levels and Fetal Macrosomia and Large for Gestational Age Babies in Women with Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis of 17,711 Women.

Gestational diabetes mellitus (GDM) is the most common metabolic disorder in pregnancy. GDM is associated with serious maternal and fetal complications, in particular, fetal macrosomia and large for gestational age (LGA), which predisposes to a higher risk of childhood obesity and type 2 diabetes mellitus later in life. Early prediction and diagnosis of GDM leads to early interventions such as diet and lifestyle, which could mitigate the maternal and fetal complications associated with GDM. Glycated haemoglobin A1c (HbA1c) has been widely used for monitoring, screening for and diagnosing diabetes and prediabetes. Increasing evidence has also showed that HbA1c could indicate fetal glucose supply. Thus, we hypothesise that the HbA1c level at around 24 to 28 weeks may predict the development of fetal macrosomia or an LGA baby in women with GDM, which could be useful for better prevention of fetal macrosomia and LGA. We searched MEDLINE, EMBASE, Cochrane and Google Scholar databases from inception to November 2022 for relevant studies that reported at least one HbA1c level during 24-28 weeks of pregnancy and fetal macrosomia or an LGA baby. We excluded studies that were not published in the English language. No other search filters were applied during the search. Two independent reviewers selected eligible studies for meta-analysis. Two independent reviewers performed data collection and analyses. The PROSPERO registration number is CRD42018086175. A total of 23 studies were included in this systematic review. Of these, 8 papers reported data of 17,711 women with GDM that allowed for inclusion in a meta-analysis. The obtained results demonstrated the prevalence of fetal macrosomia was 7.4% and of LGA, 13.36%. Meta-analyses showed that the estimated pooled risk ratio (RR) for LGA in women with high HbA1c values compared to normal or low values was 1.70 (95% CI: 1.23-2.35), p = 0.001; and the pooled RR for fetal macrosomia was 1.45 (95% CI: 0.80 to 2.63), p = 0.215. Further research is needed to evaluate the utility of HbA1c levels in predicting the delivery of a baby with fetal macrosomia or LGA in pregnant women.

Soluble Vascular Adhesion Protein 1 (sVAP-1) as a biomarker for pregnancy complications: A pilot study.

BACKGROUND: Vascular adhesion protein 1 (VAP-1) has been implicated in a wide range of clinical conditions. Moreover, serum levels are associated with disease prediction and progression in several clinical studies. There is a paucity of data on VAP-1 and pregnancy. Given the emerging role of VAP-1 in pregnancy, the aim of this study was to examine sVAP-1 as an early biomarker of pregnancy complications, especially hypertension during pregnancy. The objectives of the study are to associate sVAP-1 levels with other pregnancy complications, patient demographics and blood tests performed throughout pregnancy. METHODS: We conducted a pilot study in a cohort of pregnant women (gestational week lower than 20 at the time of recruitment) attending their first antenatal ultrasound scan at the Leicester Royal Infirmary (LRI, UK). Data were both prospectively generated (from blood sample analysis) and retrospectively collected (from hospital records). RESULTS: From July and October 2021, a total of 91 participants were enrolled. Using ELISA (enzyme-linked immunosorbent assay), we found reduced serum levels of sVAP-1 in pregnant women with either pregnancy induced hypertension (PIH) (310 ng/mL) or GDM (366.73 ng/mL) as compared to controls (427.44 ng/mL and 428.34 ng/mL, respectively). No significant difference was found between women with FGR compared to controls (424.32 ng/mL vs 424.52 ng/mL), and patients with any pregnancy complications compared to healthy pregnancies (421.28 ng/mL vs 428.34 ng/mL). CONCLUSION: Further studies are needed to establish whether or not sVAP-1 might be considered as an early, non-invasive, and affordable biomarker to screen women who will develop PIH or GDM. Our data will aid sample size calculations for such larger studies.

Blood biomarkers to predict the onset of pre-eclampsia: A systematic review and meta-analysis.

Pre-eclampsia is one of the most common pregnancy complications, and a major cause of fetal and maternal morbidity and mortality globally. Diagnosis currently takes place in the third trimester based on clinical symptoms. This systematic review and meta-analysis sought to determine the blood biomarkers that are associated with pre-eclampsia, and in particular, the biomarkers that could predict pre-eclampsia in early pregnancy. We searched the electronic databases (Medline, Embase, Cochrane Library) from inception up to March 2022. Prospective studies with 1000 or more participants that measured blood biomarkers to predict or diagnose pre-eclampsia have been included in this systematic review. Biomarkers' measurements were considered from the first up to the third trimester, but not during labor. Data concerning pre-eclampsia, biomarker measurements and study characteristics were extracted. Meta-analysis was performed when possible. We found a total of 43 studies (assessing 62 different biomarkers in 18,170 pregnancies, have been included in this systematic review, and a total of 6 studies (assessing 2 biomarkers have been included in the meta-analysis). Statistical analysis was performed for PlGF and sFlt-1. Mean difference in PlGF levels between pre-eclampsia and healthy pregnancies, appear to increase as the pregnancy progresses. Results of sFlt-1 meta-analysis were inconclusive. No significant publication bias was identified. This is the most comprehensive and up to date systematic review and meta-analysis on this important topic on blood biomarkers for the early prediction of pre-eclampsia. Further This research highlights the urgent needed for further discovery research to identify blood biomarkers that could predict the development of pre-eclampsia.

Vascular adhesion protein-1 (VAP-1) in vascular inflammatory diseases.

Vascular adhesion protein-1 (VAP-1) also known as amino oxidase copper containing 3 (AOC3) is a pro-inflammatory and versatile molecule with adhesive and enzymatic properties. VAP-1 is a primary amine oxidase belonging to the semicarbazide-sensitive amine oxidase (SSAO) family, which catalyzes the oxidation of primary amines leading to the production of ammonium, formaldehyde, methylglyoxal, and hydrogen peroxide. VAP-1 is mainly expressed by endothelial cells, smooth muscle cells, adipocytes and pericytes. It is involved in a repertoire of biological functions, e.g., immune cell extravasation, angiogenesis, and vascularization. Research into VAP-1 has intensified within the last decade on its role as a novel clinical biomarker and as a potential therapeutic target of vascular inflammatory disorders such as atherosclerosis, stroke, diabetes, neurovascular disorders (e.g., Alzheimer's Disease), hepatic disease (e.g., non-alcoholic steatohepatitis), and skin conditions (e.g., psoriasis). This is the most up-to-date and comprehensive review on VAP-1 focusing on the translational aspects of VAP-1. Compared to recent reviews, our review provides novel insights on VAP-1 and heart failure, stroke and frailty, diabetes, endometriosis, osteoarthritis, COVID-19, conjunctivitis associated systemic lupus erythematosus, hematopoietic stem cells, gliomas, treatment of colorectal cancer with a novel VAP-1 inhibitor (U-V269), promoting recovery of motor functions and habit learning with a novel VAP-1 inhibitor (PXS-4681A), and 68Ga-DOTA-Siglec-9, a labelled peptide of Siglec-9 (a VAP-1 ligand), which appears to be a safe PET tracer for inflammation in rheumatoid arthritis. Finally, we present the emerging role of VAP-1 in pregnancy as a gatekeeper of immune cells, which are critical for spiral arterial remodeling, the deficiency of which could lead to vascular disorders of pregnancy such as preeclampsia. Future research should prioritize clinical trials on VAP-1 small-molecule inhibitors and monoclonal antibodies, thus, maximizing the potential of VAP-1 targeted therapy as well as research into sVAP-1 as a clinical biomarker of diseases and its prognosis.

Proteomics Studies in Gestational Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Gestational Diabetes Mellitus (GDM) is the most common metabolic complication during pregnancy and is associated with serious maternal and fetal complications such as pre-eclampsia and stillbirth. Further, women with GDM have approximately 10 times higher risk of diabetes later in life. Children born to mothers with GDM also face a higher risk of childhood obesity and diabetes later in life. Early prediction/diagnosis of GDM leads to early interventions such as diet and lifestyle, which could mitigate the maternal and fetal complications associated with GDM. However, no biomarkers identified to date have been proven to be effective in the prediction/diagnosis of GDM. Proteomic approaches based on mass spectrometry have been applied in various fields of biomedical research to identify novel biomarkers. Although a number of proteomic studies in GDM now exist, a lack of a comprehensive and up-to-date meta-analysis makes it difficult for researchers to interpret the data in the existing literature. Thus, we undertook a systematic review and meta-analysis on proteomic studies and GDM. We searched MEDLINE, EMBASE, Web of Science and Scopus from inception to January 2022. We searched Medline, Embase, CINHAL and the Cochrane Library, which were searched from inception to February 2021. We included cohort, case-control and observational studies reporting original data investigating the development of GDM compared to a control group. Two independent reviewers selected eligible studies for meta-analysis. Data collection and analyses were performed by two independent reviewers. The PROSPERO registration number is CRD42020185951. Of 120 articles retrieved, 24 studies met the eligibility criteria, comparing a total of 1779 pregnant women (904 GDM and 875 controls). A total of 262 GDM candidate biomarkers (CBs) were identified, with 49 CBs reported in at least two studies. We found 22 highly replicable CBs that were significantly different (nine CBs were upregulated and 12 CBs downregulated) between women with GDM and controls across various proteomic platforms, sample types, blood fractions and time of blood collection and continents. We performed further analyses on blood (plasma/serum) CBs in early pregnancy (first and/or early second trimester) and included studies with more than nine samples (nine studies in total). We found that 11 CBs were significantly upregulated, and 13 CBs significantly downregulated in women with GDM compared to controls. Subsequent pathway analysis using Database for Annotation, Visualization and Integrated Discovery (DAVID) bioinformatics resources found that these CBs were most strongly linked to pathways related to complement and coagulation cascades. Our findings provide important insights and form a strong foundation for future validation studies to establish reliable biomarkers for GDM.

Effects of Supervised Exercise on the Development of Hypertensive Disorders of Pregnancy: A Systematic Review and Meta-Analysis.

Hypertensive disorders of pregnancy (HDP) are the most common medical complication in pregnancy, affecting approximately 10-15% of pregnancies worldwide. HDP are a major cause of maternal and perinatal morbidity and mortality, and each year, worldwide, around 70,000 mothers and 500,000 babies die because of HDP. Up-to-date high-quality systematic reviews quantifying the role of exercise and the risks of developing HDP are currently lacking. Physical exercise is considered to be safe and beneficial to pregnant women. Supervised exercise has been shown to be safe and to be more beneficial than unsupervised exercise in the general population, as well as during pregnancy in women with obesity and diabetes. Therefore, we undertook a systematic review and meta-analysis to investigate the effects of women performing supervised exercise during pregnancy compared to a control group (standard antenatal care or unsupervised exercise) on the development of HDP. We searched Medline, Embase, CINHAL, and the Cochrane Library, which were searched from inception to December 2021. We included only randomized controlled trials (RCTs) investigating the development of HDP compared to a control group (standard antenatal care or unsupervised exercise) in pregnant women performing supervised exercise. Two independent reviewers selected eligible trials for meta-analysis. Data collection and analyses were performed by two independent reviewers. The PROSPERO registration number is CRD42020176814. Of 6332 articles retrieved, 16 RCTs met the eligibility criteria, comparing a total of 5939 pregnant women (2904 pregnant women in the intervention group and 3035 controls). The risk for pregnant women to develop HDP was significantly reduced in the intervention compared to the control groups, with an estimated pooled cumulative incidence of developing HDP of 3% in the intervention groups (95% CI: 3 to 4) and of 5% in the control groups (95% CI: 5 to 6), and a pooled odds ratio (OR) comparing intervention to control of 0.54 (95% CI:0.40 to 0.72, p < 0.001). A combination of aerobic and anaerobic exercise, or yoga alone, had a greater beneficial effect compared to performing aerobic exercise only (mixed-OR = 0.50, 95% CI:0.33 to 0.75, p = 0.001; yoga-OR = 0.28, 95% CI:0.13 to 0.58, p = 0.001); aerobic exercise only-OR = 0.87, 95% CI:0.55 to 1.37, p = 0.539). Pregnancy is an opportunity for healthcare providers to promote positive health activities, thus optimizing the health of pregnant women with potential short- and long-term benefits for both mother and child. This systematic review and meta-analysis support a beneficial effect of either structured exercise (combination of aerobic, strength, and flexibility workouts) or yoga for preventing the onset of HDP. Yoga, considered a low-impact physical activity, could be more acceptable and safer for women in pregnancy in reducing the risk of developing HDP.

Vascular Adhesion Protein-1 Determines the Cellular Properties of Endometrial Pericytes.

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible adhesion molecule and a primary amine oxidase involved in immune cell trafficking. Leukocyte extravasation into tissues is mediated by adhesion molecules expressed on endothelial cells and pericytes. Pericytes play a major role in the angiogenesis and vascularization of cycling endometrium. However, the functional properties of pericytes in the human endometrium are not known. Here we show that pericytes surrounding the spiral arterioles in midluteal human endometrium constitutively express VAP-1. We first characterize these pericytes and demonstrate that knockdown of VAP-1 perturbed their biophysical properties and compromised their contractile, migratory, adhesive and clonogenic capacities. Furthermore, we show that loss of VAP-1 disrupts pericyte-uterine natural killer cell interactions in vitro. Taken together, the data not only reveal that endometrial pericytes represent a cell population with distinct biophysical and functional properties but also suggest a pivotal role for VAP-1 in regulating the recruitment of innate immune cells in human endometrium. We posit that VAP-1 could serve as a potential biomarker for pregnancy pathologies caused by a compromised perivascular environment prior to conception.

Improving Uptake of Postnatal Checking of Blood Glucose in Women Who Had Gestational Diabetes Mellitus in Universal Healthcare Settings: A Systematic Review.

The aim of this systematic review is to look at the barriers to uptake and interventions to improve uptake of postnatal screening in women who have had gestational diabetes mellitus (GDM). Increasing postnatal screening rates could lead to timely interventions that could reduce the incidence of type 2 diabetes mellitus (T2DM), the associated long-term health complications, and the financial burden of T2DM. A systematic review of the literature was undertaken. PubMed, Embase, Medline, CINAHL and the Cochrane library databases were searched using well-defined search terms. Predefined inclusion and exclusion criteria were used to identify relevant manuscripts. Data extractions and quality assessments were performed by one reviewer and checked by a second reviewer. Eleven primary studies of various research design and three systematic reviews were included. We identified seven themes within these studies and these were described in two categories, barriers and interventions. There appeared to be no single intervention that would overcome all the identified barriers, however, reminders to women and healthcare professionals appear to be most effective. Uptake rates of testing for T2DM are low in women with GDM. Interventions developed with consideration of the identified barriers to uptake could promote greater numbers of women attending for follow-up.

Circulating C1q complement/TNF-related protein (CTRP) 1, CTRP9, CTRP12 and CTRP13 concentrations in Type 2 diabetes mellitus: In vivo regulation by glucose.

OBJECTIVES: The C1q complement/TNF-related protein (CTRP) superfamily, which includes the adipokine adiponectin, has been shown in animal models to have positive metabolic and cardiovascular effects. We sought to investigate circulating CTRP1, CTRP9, CTRP12 and CTRP13 concentrations in persons with type 2 diabetes mellitus (T2DM), with age and BMI matched controls, and to examine the effects of a 2 hour 75g oral glucose tolerance test (OGTT) on serum CTRP1, CTRP9, CTRP12 and CTRP13 levels in persons with T2DM. DESIGN: Cross-sectional study [newly diagnosed T2DM (n = 124) and control (n = 139) participants]. Serum CTRP1, CTRP9, CTRP12 and CTRP13 were measured by ELISA. RESULTS: Systolic and diastolic blood pressure, total cholesterol (TCH), Low-density lipoprotein (LDL)-cholesterol, triglycerides, TCH/High-density lipoprotein (HDL) ratio, triglycerides/HDL ratio, glucose, insulin, homeostatic model assessment-insulin resistance (HOMA-IR), C-reactive protein and endothelial lipase were significantly higher, whereas leptin and adiponectin were significantly lower in T2DM participants. Serum CTRP1 were significantly higher and CTRP12 significantly lower in T2DM participants. Age, diastolic blood pressure, glucose and CTRP12 were predictive of serum CTRP1; leptin was predictive of serum CTRP9; glucose and CTRP1 were predictive of serum CTRP12; endothelial lipase was predictive of serum CTRP13. Finally, serum CTRP1 were significantly higher and CTRP12 significantly lower in T2DM participants after a 2 hour 75g OGTT. CONCLUSIONS: Our data supports CTRP1 and CTRP12 as potential novel biomarkers for the prediction and early diagnosis of T2DM. Furthermore, pharmacological agents that target CTRP1 and CTRP12 could represent a new strategy in the treatment of T2DM.

Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation.

BACKGROUND: Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. OBJECTIVE: To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin. SOURCES: MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions. METHODS: Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers. RESULTS: We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP). LIMITATIONS: There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking. CONCLUSIONS: Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Boehringer Ingelheim, Bracknell, UK). FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Elevated soluble CD163 in gestational diabetes mellitus: secretion from human placenta and adipose tissue.

Recently soluble CD163 (sCD163), a cleaved form of the macrophage receptor CD163, was identified as a macrophage-specific risk-predictor for developing Type 2 Diabetes. Here, we investigate circulating levels of sCD163 in gestational diabetes mellitus (GDM). Furthermore, given the role of the placenta in the pathogenesis of GDM, we assessed placental contribution to sCD163 secretion. Paired maternal (venous) and umbilical vein blood samples from GDM (n = 18) and Body Mass Index (BMI) matched control women (n = 20) delivered by caesarean section at 39-40 week gestation were assessed for circulating levels of sCD163, Tumour necrosis factor alpha (TNF-α) and Interleukin 6 (IL-6). Media from explant culture of maternal subcutaneous fat and corresponding placental tissues were assayed for these same molecules. CD163 positive cell numbers were determined in placental and adipose tissues of GDM and control women. We found significantly elevated circulating sCD163 levels in GDM mothers (688.4±46.9 ng/ml vs. 505.6±38.6 ng/ml) and their offspring (418.2±26.6 ng/ml vs. 336.3±24.4 ng/ml [p<0.05 for both]) as compared to controls, together with elevated circulating TNF-α and IL-6 levels. Moreover, both GDM placentae (268.1±10.8 ng/ml/mg vs. 187.6±20.6 ng/ml/mg) and adipose explants (41.1±2.7 ng/ml/mg vs. 26.6±2.4 ng/ml/mg) released significantly more sCD163 than controls. Lastly, significantly more CD163 positive cells were observed in GDM placentae (25.7±1.1 vs. 22.1±1.2) and adipose tissue (19.1±1.1 vs 12.7±0.9) compared to controls. We describe elevated sCD163 levels in GDM and identify human placenta as a novel source of sCD163 suggesting that placental tissues might contribute to the increased levels of circulating sCD163 in GDM pregnancies.