Inflammatory Aetiology of Human Myometrial Activation Tested Using Directed Graphs

There are three main hypotheses for the activation of the human uterus at labour: functional progesterone withdrawal, inflammatory stimulation, and oxytocin receptor activation. To test these alternatives we have taken information and data from the literature to develop causal pathway models for the activation of human myometrium. The data provided quantitative RT-PCR results on key genes from samples taken before and during labour. Principal component analysis showed that pre-labour samples form a homogenous group compared to those during labour. We therefore modelled the alternative causal pathways in non-labouring samples using directed graphs and statistically compared the likelihood of the different models using structural equations and D-separation approaches. Using the computer program LISREL, inflammatory activation as a primary event was highly consistent with the data (p = 0.925), progesterone withdrawal, as a primary event, is plausible (p = 0.499), yet comparatively unlikely, oxytocin receptor mediated initiation is less compatible with the data (p = 0.091). DGraph, a software program that creates directed graphs, produced similar results (p = 0.684, p = 0.280, and p = 0.04, respectively). This outcome supports an inflammatory aetiology for human labour. Our results demonstrate the value of directed graphs in determining the likelihood of causal relationships in biology in situations where experiments are not possible

Moxibustion for cephalic version: a feasibility randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Moxibustion (a type of Chinese medicine which involves burning a herb close to the skin) has been used to correct a breech presentation. Evidence of effectiveness and safety from systematic reviews is encouraging although significant heterogeneity has been found among trials. We assessed the feasibility of conducting a randomised controlled trial of moxibustion plus usual care compared with usual care to promote cephalic version in women with a breech presentation, and examined the views of women and health care providers towards implementing a trial within an Australian context.</p> <p>Methods</p> <p>The study was undertaken at a public hospital in Newcastle, New South Wales, Australia. Women at 34-36.5 weeks of gestation with a singleton breech presentation (confirmed by ultrasound), were randomised to moxibustion plus usual care or usual care alone. The intervention was administered over 10 days. Clinical outcomes included cephalic presentation at birth, the need for ECV, mode of birth; perinatal morbidity and mortality, and maternal complications. Feasibility outcomes included: recruitment rate, acceptability, compliance and a sample size for a future study. Interviews were conducted with 19 midwives and obstetricians to examine the acceptability of moxibustion, and views on the trial.</p> <p>Results</p> <p>Twenty women were randomised to the trial. Fifty one percent of women approached accepted randomisation to the trial. A trend towards an increase in cephalic version at delivery (RR 5.0; 95% CI 0.7-35.5) was found for women receiving moxibustion compared with usual care. There was also a trend towards greater success with version following ECV. Two babies were admitted to the neonatal unit from the moxibustion group. Compliance with the moxibustion protocol was acceptable with no reported side effects. Clinicians expressed the need for research to establish the safety and efficacy of moxibustion, and support for the intervention was given to increase women's choices, and explore opportunities to normalise birth. The sample size for a future trial is estimated to be 381 women.</p> <p>Conclusion</p> <p>Our findings should be interpreted with caution as the study was underpowered to detect statistical differences between groups. Acceptance by women and health professionals towards moxibustion suggest further research is warranted.</p> <p>Trial Registration</p> <p>Australia and New Zealand Clinical Trials Register (ANZCTR): <a href="http://www.anzctr.org.au/ACTRN12609000985280.aspx">ACTRN12609000985280</a></p

The endocrine regulation of human labour

Placental corticotrophin releasing hormone (CRH) determines the length of pregnancy. CRH drives fetal adrenal production of dehydroepiandrosterone sulfate (DHEAS). DHEAS is converted into estriol in the placenta. Estriol and estradiol are competitive antagonists at equimolar concentrations but both are estrogen agonists at high concentrations. Labor is associated with an excess of estriol over estradiol. High levels of estriol lead to myometrial expression of connexin 43 and cyclo-oxygenase. Myometrial expression of connexin 43 and prostaglandins leads to synchronised myometrial contractions and the onset of labor

Directed Graphs of Messenger RNA Abundances in Human Myometrium

<p>Three models were generated and are represented in the following graphics. (A) Does progesterone withdrawal initiate labour? (B) Does inflammation initiate labour? (C) Does oxytocin receptor mediate onset of labour?</p

Messenger RNA Abundances in Human Myometrium

<p>Box and whisker plots of mRNA abundances of PRA and PRB, ERα, ERβ, IL-8, COX-2, MnSOD, β2-microglobulin (β2μ), connexin-43 (CX-43), OTR, and the homeobox gene HoxA10 in labouring (L) and non-labouring (N) women.</p

Alterations of placental vascular function in asthmatic pregnancies

Asthma during pregnancy is associated with low-birthweight neonates at term but the mechanisms that cause this outcome are presently unknown. Changes in placental vascular function resulting from asthma or its treatment could contribute to altered fetal growth. We have prospectively followed women with asthma and a control group of women without asthma during their pregnancies, classified them based on asthma severity and glucocorticoid intake, and monitored fetal development and placental blood flow using Doppler ultrasound at 18 and 30 wk gestation. The placentae from these women were collected after delivery and vascular responses to dilator and constrictor agonists assessed using an in vitro placental perfusion method. At 18 wk gestation, umbilical artery flow velocity waveforms were significantly reduced in the moderate and severe asthmatic groups and in those women using high-dose inhaled glucocorticoid for the treatment of their asthma (ANOVA, p 0.05). Corticotropin-releasing hormone (CRH), a potent vasodilator that acts via the nitric oxide pathway, caused a dose-dependent vasodilatory response in all placentae in vitro. However, CRH-induced dilation was significantly reduced in moderate and severe asthmatics (ANOVA, p < 0.05). Vasoconstrictor responses to potassium chloride and prostaglandin F2alpha were reduced in placentae from moderate and severe asthmatic women (ANOVA, p < 0.05). These studies demonstrate significant differences in placental vascular function in pregnancies complicated by asthma, which may relate directly to the asthma or be a consequence of the associated glucocorticoid treatment. These changes in vascular function in asthmatic pregnancies may contribute to the low-birthweight outcome observed in this condition.Vicki L. Clifton, Warwick B. Giles, Roger Smith, Andrew T. Bisits, Philip A. J. Hempenstall, Carolyn G. Kessell, and Peter G. Gibso

Patterns of plasma corticotropin-releasing hormone, progesterone, estradiol, and estriol change and the onset of human labor

Context: Clinical prediction of preterm delivery is largely ineffective, and the mechanism mediating progesterone (P) withdrawal and estrogen activation at the onset of human labor is unclear. Objectives: Our objectives were to determine associations of rates of change of circulating maternal CRH in midpregnancy with preterm delivery, CRH with estriol (E3) concentrations in late pregnancy, and predelivery changes in the ratios of E3, estradiol (E2), and P. Design and Setting: A cohort of 500 pregnant women was followed from first antenatal visits to delivery during the period 2000–2004 at John Hunter Hospital, New South Wales, Australia, a tertiary care obstetric hospital. Patients: Unselected subjects were recruited (including women with multiple gestations) and serial blood samples obtained. Main Outcome Measures: CRH daily percentage change in term and preterm singletons at 26 wk, ratios E3/E2, P/E3, and P/E2 and the association between E3 and CRH concentrations in the last month of pregnancy (with spontaneous labor onset) were assessed. Results: CRH percentage daily change was significantly higher in preterm than term singletons at 26 wk (medians 3.09 and 2.73; P = 0.003). In late pregnancy, CRH and E3 concentrations were significantly positively associated (P = 0.003). E3/E2 increased, P/E3 decreased, and P/E2 was unchanged in the month before delivery (medians: E3/E2, 7.04 and 10.59, P < 0.001; P/E3, 1.55 and 0.98, P < 0.001; P/E2, 11.78 and 10.79, P = 0.07). Conclusions: The very rapid rise of CRH in late pregnancy is associated with an E3 surge and critically altered P/E3 and E3/E2 ratios that create an estrogenic environment at the onset of labor. Our evidence provides a rationale for the use of CRH in predicting preterm birth and informs approaches to delaying labor using P supplementation