Non-hypertensive gestational diabetes mellitus: Placental histomorphology and its association with perinatal outcomes.

INTRODUCTION: Gestational diabetes mellitus (GDM) exerts a great impact on the placenta and reflects changes on placentas both morphological and functionally. The aims of this study are to evaluate the prevalence of placental histopathological lesions in pregnancies complicated by GDM compared to gestational age-matched controls, and their association with maternal and fetal complications. METHODS: Fifty-four singleton GDM-complicated pregnancies were recruited and compared to 33 consecutive normal pregnancies. Two pathologists, blinded to all clinical data, reviewed and evaluated all histological samples of the placentas in accordance with Amsterdam criteria. Relevant demographic, clinical data and primary birth outcomes were recorded. RESULTS: A myriad of histomorphological abnormalities, including chronic inflammation (n = 9/54, p = 0.031), histological chorioamnionitis (n = 23/54, p < 0.001), umbilical/chorionic vasculitis (n = 9/54, p = 0.031), changes related to maternal vascular malperfusion (n = 22/54, p = 0.003), chorangiosis (n = 10/54, p = 0.046) and villous dysmaturity (n = 9/54, p = 0.012) were observed more frequently in the GDM placentas compared to the controls. Additionally, GDM significantly increased the risk of fetal complications, including macrosomia/fetal growth restriction (n = 13/54, p = 0.004). DISCUSSION: Histoarchitectural abnormalities were observed more frequently in placentas of GDM pregnancies compared to the controls. Our findings support the hypothesis that diabetic-induced damage in the placental function may be associated with the increased in fetal growth disorders in GDM-complicated pregnancies.

Is alternate day dosing of oral iron an effective option for iron-deficiency anaemia?

Commentary on: Kaundal R, Bhatia P, Jain A, et al. Randomized controlled trial of twice-daily versus alternate-day oral iron therapy in the treatment of iron-deficiency anemia. Ann Hematol. 2020;99:57-63. Series Editor: Dr Teck Khong, DTB Associate Editor, Clinical Pharmacology, St George's, University of London, UK.

Diagnostic Utility of TSSC3 and RB1 Immunohistochemistry in Hydatidiform Mole.

The general notion of complete hydatidiform moles is that most of them consist entirely of paternal DNA; hence, they do not express p57, a paternally imprinted gene. This forms the basis for the diagnosis of hydatidiform moles. There are about 38 paternally imprinted genes. The aim of this study is to determine whether other paternally imprinted genes could also assist in the diagnostic approach of hydatidiform moles. This study comprised of 29 complete moles, 15 partial moles and 17 non-molar abortuses. Immunohistochemical study using the antibodies of paternal-imprinted (RB1, TSSC3 and DOG1) and maternal-imprinted (DNMT1 and GATA3) genes were performed. The antibodies' immunoreactivity was evaluated on various placental cell types, namely cytotrophoblasts, syncytiotrophoblasts, villous stromal cells, extravillous intermediate trophoblasts and decidual cells. TSSC3 and RB1 expression were observed in all cases of partial moles and non-molar abortuses. In contrast, their expression in complete moles was identified in 31% (TSSC3) and 10.3% (RB1), respectively (p < 0.0001). DOG1 was consistently negative in all cell types in all cases. The expressions of maternally imprinted genes were seen in all cases, except for one case of complete mole where GATA3 was negative. Both TSSC3 and RB1 could serve as a useful adjunct to p57 for the discrimination of complete moles from partial moles and non-molar abortuses, especially in laboratories that lack comprehensive molecular service and in cases where p57 staining is equivocal.

Dapagliflozin in people with chronic kidney disease.

Commentary on: Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46. Series Editor: Dr Teck Khong, DTB Associate Editor, Clinical Pharmacology, St George's, University of London, UK.

What does the TIME study tell us about morning and evening dosing of antihypertensive medication?

Commentary on: Mackenzie IS, Rogers A, Poulter NR, et al Cardiovascular outcomes in adults with hypertension with evening vs morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet 2022;400:1417-25.

Evidence for empagliflozin in heart failure with preserved ejection fraction (HFpEF).

Commentary on: Anker SD, Butler J, Filippatos G, et al Empagliflozin in heart failure with a preserved ejection fraction. New England Journal of Medicine, 2021; 385:1451-61.

Short-term effect of deprescribing antihypertensives in older people.

Commentary on: Sheppard JP, Burt J, Lown M, et al Effect of antihypertensive medication reduction vs usual care on short-term blood pressure control in patients with hypertension aged 80 years and older: The OPTIMISE randomized clinical trial. JAMA 2020;323:2039-51.Series co-ordinator: Dr Teck Khong, DTB Associate Editor, Clinical Pharmacology, St George's, University of London, UK.

Treating hypertension with a pill containing very low doses of four antihypertensive agents compared with standard dose irbesartan.

Commentary on: Chow CK, Atkins ER, Hillis GS, et al Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial. Lancet 2021;398:1043-52. Series co-ordinator: Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, UK.

Gardnerella vaginalis infection in pregnancy: Effects on placental development and neonatal outcomes.

INTRODUCTION: Gardnerella vaginalis (GV)-associated bacterial vaginosis is recognised for its detrimental effects on pregnancy resulting in poor obstetric and neonatal outcomes. There is limited knowledge of the effects on placental histomorphology following GV infection in pregnancy. We investigated the effects of GV infection on the placenta, particularly with regards to the syncytiotrophoblasts and vascular development, and related these to neonatal outcomes. METHODS: A prospective cohort study involving GV-positive pregnant women presented with abnormal vaginal discharge, with gestational age-matched healthy pregnant women controls. Placental sampling was performed upon delivery and examined histologically. Vascular endothelial growth factor-A (VEGF-A) and hypoxia-inducible factor-1α (HIF-1α) mRNA and protein expression were analysed by real-time PCR and immunohistochemistry respectively. The standard measures in neonatal outcomes were recorded. RESULTS: Placentas from GV-positive mothers were found to have significant histological evidence of maternal and/or fetal inflammatory response compared with the controls (17/28: 60.7% vs 2/20: 10%) (p = 0.0011). There was an increase in the percentage of syncytial nuclear aggregates (SNAs) per villus (47.4 ± 11.09%) in placentas from GV-positive mothers (p < 0.0001). VEGF-A was significantly increased in specifically, the villous endothelial cells of placentas with GV infection, but no difference in the immunoexpression of HIF-1α in these cells between groups. However, these were not associated with adverse neonatal outcomes. DISCUSSION: Increased placental VEGF-A expression associated with increased SNAs in pregnant women with GV infection of the genital tract may be an intrauterine response towards placental vascular remodeling, that may also serve as a protective role in moderating birth outcomes.

What role for PCI in stable ischaemic heart disease?

Commentary on: Maron DJ, Hochman JS, Reynolds HR, et al Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med 2020;382:1395-1407.Series co-ordinator: Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, UK.

A Review of Placenta and Umbilical Cord-Derived Stem Cells and the Immunomodulatory Basis of Their Therapeutic Potential in Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a devastating lung disorder of preterm infants as a result of an aberrant reparative response following exposures to various antenatal and postnatal insults. Despite sophisticated medical treatment in this modern era, the incidence of BPD remains unabated. The current strategies to prevent and treat BPD have met with limited success. The emergence of stem cell therapy may be a potential breakthrough in mitigating this complex chronic lung disorder. Over the last two decades, the human placenta and umbilical cord have gained increasing attention as a highly potential source of stem cells. Placenta-derived stem cells (PDSCs) and umbilical cord-derived stem cells (UCDSCs) display several advantages such as immune tolerance and are generally devoid of ethical constraints, in addition to their stemness qualities. They possess the characteristics of both embryonic and mesenchymal stromal/stem cells. Recently, there are many preclinical studies investigating the use of these cells as therapeutic agents in neonatal disease models for clinical applications. In this review, we describe the preclinical and clinical studies using PDSCs and UCDSCs as treatment in animal models of BPD. The source of these stem cells, routes of administration, and effects on immunomodulation, inflammation and regeneration in the injured lung are also discussed. Lastly, a brief description summarized the completed and ongoing clinical trials using PDSCs and UCDSCs as therapeutic agents in preventing or treating BPD. Due to the complexity of BPD, the development of a safe and efficient therapeutic agent remains a major challenge to both clinicians and researchers.

Prospective cohort study: Causes of stillbirth in Australia 2013-2018.

BACKGROUND: Stillbirth is a major public health problem that is slow to improve in Australia. Understanding the causes of stillbirth through appropriate investigation is the cornerstone of prevention and important for parents to understand why their baby died. AIM: The aim of this study is to assess compliance with the Perinatal Society of Australia and New Zealand (PSANZ) Perinatal Mortality Clinical Practice Guidelines (2009) for stillbirths. METHODS: This is a prospective multi-centred cohort study of stillbirths at participating hospitals (2013-2018). Data were recorded into a purpose-built database. The frequency of the recommended core investigations was calculated, and χ2 test was performed for subgroup analyses by gestational age groups and timing of fetal death. A 70% compliance threshold was defined for investigations. The cause of death categories was provided according to PSANZ Perinatal Death Classification. RESULTS: Among 697 reported total stillbirths, 562 (81%) were antepartum, and 101 (15%) were intrapartum. The most common cause of death categories were 'congenital abnormality' (12.5%), 'specific perinatal conditions' (12.2%) and 'unexplained antepartum death' (29%). According to 2009 guidelines, there were no stillbirths where all recommended investigations were performed (including or excluding autopsy). A compliance of 70% was observed for comprehensive history (82%), full blood count (94%), cytomegalovirus (71%), toxoplasmosis (70%), renal function (75%), liver function (79%), external examination (86%), post-mortem examination (84%) and placental histopathology (92%). The overall autopsy rate was 52%. CONCLUSIONS: Compliance with recommended investigations for stillbirth was suboptimal, and many stillbirths remain unexplained. Education on the value of investigations for stillbirth is needed. Future studies should focus on understanding the yield and value of investigations and service delivery gaps that impact compliance.

Effect of PCI of culprit and non-culprit lesions for patients with STEMI compared with culprit lesion-only PCI.

Commentary on: Mehta SR, Wood DA, Storey RF, et al Complete Revascularization with Multivessel PCI for Myocardial Infarction. N Engl J Med 2019; 381:1411-21. Commentary by: Dr Emma Magavern and Dr Teck Khong Clinical Pharmacology, St George's, University of London, UK. Series Editor: Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, UK.

Effect of dapagliflozin in patients with heart failure.

Commentary on: McMurray JJV, Solomon SD, Inzucchi SE, et al Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008. Commentary by: Dr Joshua Au Yeunga, Clinical Pharmacology, St Thomas' Hospital, London, UK and Dr Teck Khong, Clinical Pharmacology, St George's, University of London, UK. Series Editor: Dr Teck Khong, DTB Associate Editor, Clinical Pharmacology, St George's, University of London, UK.