Penelope M. Sheehan

Vessel remodelling, pregnancy hormones and extravillous trophoblast function

During early human pregnancy, extravillous trophoblast (EVT) cells from the placenta invade the uterine decidual spiral arterioles and mediate the remodelling of these vessels such that a low pressure, high blood flow can be supplied to the placenta. This is essential to facilitate normal growth and development of the foetus. Defects in remodelling can manifest as the serious pregnancy complication pre-eclampsia. During the period of vessel remodelling three key pregnancy-associated hormones, human chorionic gonadotrophin (hCG), progesterone (P(4)) and oestradiol (E(2)), are found in high concentrations at the maternal-foetal interface. Potentially these hormones may control EVT movement and thus act as regulators of vessel remodelling. This review will discuss what is known about how these hormones affect EVT proliferation, migration and invasion during vascular remodelling and the potential relationship between hCG, P(4), E(2) and the development of pre-eclampsia.

Maternal Thyroid Disease and Preterm Birth: Systematic Review and Meta-Analysis

CONTEXT Thyroid disease in pregnancy is increasing with rising average maternal ages in developed countries. The evidence for an association between preterm birth and thyroid disease has been confounded by small studies with varying outcomes and methodology. OBJECTIVE The aim of this meta-analysis is to review the literature regarding thyroid disease including subclinical and overt hypothyroidism, hyperthyroidism, and isolated hypothyroxinemia and the specific outcome of preterm birth. DATA SOURCES A search of PubMed and Embase databases was performed in May 2015. A fixed-effects model was used to calculate the overall combined odds ratio (OR) with its corresponding 95% confidence interval (95% CI) to evaluate the relationship between thyroid disease and preterm delivery. STUDY SELECTION Studies were considered eligible if they met the following criteria: prospective cohort study or a case control study; the exposure of interest was maternal thyroid disease, including subclinical hypothyroidism, overt hypothyroidism, hyperthyroidism, or isolated hypothyroxinemia; the outcome of interest was preterm delivery; and data regarding numbers of preterm births in each cohort were reported. DATA EXTRACTION Data were recorded in a database evidence table including any incidence data for maternal thyroid disease and preterm birth compared to a reference group. DATA SYNTHESIS Fourteen cohort studies and one case control study involving 2 532 704 participants were included. The combined OR of preterm delivery for pregnant women with overt hypothyroidism compared with the reference group was 1.19 (95% CI, 1.12-1.26; P < .00001). There was also a significant risk of preterm birth in women with hyperthyroidism (OR, 1.24 [95%, CI 1.17-1.31]; P < .00001). Subclinical hypothyroidism and isolated hypothyroxinemia showed no significant increase in OR. Sensitivity analysis made no change to these results. CONCLUSION Both overt hypothyroidism and hyperthyroidism are associated with a small but statistically significant increase in OR for preterm birth not seen in subclinical hypothyroidism or isolated hypothyroxinemia.

Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women

Human ether-a-go-go-related gene (hERG) potassium channels determine cardiac action potential and contraction duration. Human uterine contractions are underpinned by an action potential that also possesses an initial spike followed by prolonged depolarization. Here we show that hERG channel proteins (α-conducting and β-inhibitory subunits) and hERG currents exist in isolated patch-clamped human myometrial cells. We show that hERG channel activity suppresses contraction amplitude and duration before labour, thereby facilitating quiescence. During established labour, expression of β-inhibitory protein is markedly enhanced, resulting in reduced hERG activity that is associated with an increased duration of uterine action potentials and contractions. Thus, changes in hERG channel activity contribute to electrophysiological mechanisms that produce contractions during labour. We also demonstrate that this system fails in women with elevated BMI, who have enhanced hERG activity as a result of low β-inhibitory protein expression, which likely contributes to the weak contractions and poor labour outcomes observed in many obese women necessitating caesarean delivery.

A possible role for progesterone metabolites in human parturition

There has been a recent resurgence of interest in the role of progesterone in the maintenance of human pregnancy and the onset of labour, following recent reports of its use to prevent preterm labour in high‐risk patients. One possible mechanism by which progesterone might contribute to uterine quiescence is through the actions of its metabolites. This article provides a brief overview of progesterone in human pregnancy and an outline of progesterone metabolism in the various reproductive tract tissues as well as the evidence for actions of progesterone metabolites in pregnancy.

Early origins of mental disorder - risk factors in the perinatal and infant period

BackgroundThere is increasing understanding of the significance of early neurodevelopment in establishing risk for the range of mental disorders. Models of the early aetiology of mental disorders are complex with a range of potential factors from genetic and epigenetic to environmental influencing neurological and psychological development. Whilst the mechanisms are not fully understood, this paper provides an overview of potential biological and neurobiological factors that might be involved.MethodAn aetiological model is presented and discussed. The discussion includes a range of risk factors for mental disorder. Maternal anxiety disorder is presented and reviewed as an example of the interaction of placental, epigenetic and early parenting factors elevating risk of poor neonatal outcome.ResultsAvailable evidence points to the importance of in-utero influences as well as the role of early attachment and emotional care. Transgenerational mechanisms such as the impact of maternal mental disorder on foetal development are important models for examination of early risk. Maternal anxiety, as an example, is a significant risk factor for compromised mental health.ConclusionsDevelopment of models for understanding the early origins of mental disorder is an important step in elaborating risk reduction strategies. Comprehensive early identification of risk raises the possibility of preventive interventions.

Homeobox gene Distal-Less 3 is a regulator of villous cytotrophoblast differentiation and its expression is increased in human idiopathic foetal growth restriction

Human idiopathic foetal growth restriction (FGR) is frequently associated with placental insufficiency. In our previous studies, we have reported the isolation and characterisation of the homeobox gene Distal-less 3 (DLX3) in the human placenta. In this study, we have investigated the level of DLX3 expression in idiopathic FGR-affected placentae and determined its functional role in villous trophoblast differentiation. FGR-affected placentae (n = 25) were collected based on well-defined clinical criteria and matched for gestation with control uncomplicated pregnancies (n = 25). Real-time polymerase chain reaction and immunoblotting showed increased DLX3 mRNA and protein expression in FGR-affected placentae compared with gestation-matched controls. Qualitative immunohistochemistry revealed DLX3 localisation in the syncytiotrophoblast, cytotrophoblasts and endothelial cells surrounding the foetal capillaries in both FGR-affected and control placentae. Down-regulation of DLX3 in primary villous trophoblast cells and a trophoblast-derived cell line showed decreased expression of differentiation markers, 3βHSD, βhCG and syncytin. Therefore, we conclude that increased DLX3 expression in FGR may contribute to trophoblast dysfunction observed in FGR.

Correlates of Chlamydia trachomatis infection in a primary care sentinel surveillance network

BACKGROUND Chlamydia is the most commonly notified infection in Australia. Prevention strategies should be informed by routine data on at-risk populations. METHODS We calculated chlamydia positivity and correlates of infection using multivariable logistic regression for data collected between April 2006 and June 2009. RESULTS Chlamydia positivity was 5.6% in 12233 females, 7.7% in 10316 heterosexual males and 6.2% in 7872 men who have sex with men (MSM). Correlates of chlamydia positivity among females included younger age (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.92-2.69), being born overseas (OR 1.50, 95% CI 1.25-1.82), multiple sex partners in the past year (OR 1.72, 95% CI 1.40-2.11) and inconsistent condom use with regular sex partners (OR 3.44 ,95% CI 1.65-7.20). Sex work was protective for females (OR 0.68, 95% CI 0.53-0.86). Among heterosexual males, correlates of positivity were younger age (OR 1.87, 95% CI 1.62-2.17), being born overseas (OR 1.35, 95% CI 1.16-1.58), symptoms at the time of testing (OR 1.64, 95% CI 1.40-1.92) and multiple sex partners in the past year (OR 1.83, 95% CI 1.46-2.30). Correlates of positivity among MSM were being born overseas (OR 1.23, 95% CI 1.00-1.51), being HIV-positive (OR 1.80, 95%CI 1.32-2.47), and reporting six or more anal sex partners in the past 6 months (OR 4.45, 95% CI 1.37-14.5). CONCLUSIONS Our analysis identified subgroups at the highest risk of chlamydia in Victoria. These estimates will provide important baseline information to measure the impact of chlamydia control strategies.

Cervical length as a predictor for spontaneous preterm birth in high-risk singleton pregnancy: current knowledge.

†The University of Melbourne, Department of Obstetrics and Gynaecology, The Royal Women’s Hospital, Locked Bag 300, Parkville, Victoria 3052, Australia; ‡Pregnancy Research Centre, Department of Maternal-Fetal Medicine, The Royal Women’s Hospital, Parkville, Victoria, Australia; §Department of Obstetrics, Paulista School of Medicine Federal University of São Paulo, São Paulo, Brazil *Correspondence. (e-mail: Fabricio.Costa@thewomens.org.au)

Factors associated with spontaneous preterm birth risk assessed by transvaginal ultrasound following cervical cerclage.

To determine the predictive value of various cervical length measurements postcerclage for the outcome of preterm birth following both elective and rescue cerclage.

Outcomes and predictive tests from a dedicated specialist clinic for women at high risk of preterm labour: A ten year audit

Preterm birth continues to be a major cause of infant morbidity and mortality worldwide, but advances have recently been made in its prediction and prevention. A short cervix (<25 mm) in the second trimester on transvaginal ultrasound scan and fetal fibronectin are important predictive tests. For over ten years, the Preterm Labour Clinic at the Royal Womens Hospital, Melbourne, Australia has provided care for women at high risk of preterm birth, including those with a previous preterm birth, previous cervical surgery, uterine malformation or incidental finding of short cervix at routine ultrasound. The purpose of this study was to review this clinics outcomes for the first decade.