Robert Ogle

Guidelines for the use of recombinant activated factor VII in massive obstetric haemorrhage

Recombinant activated factor VII (rFVIIa) is emerging as a novel therapy for the treatment of life or fertility‐threatening post‐partum haemorrhage (PPH) unresponsive to standard therapy that in some cases may prevent the need for peripartum hysterectomy. The level of evidence to date for use of rFVIIa in PPH is limited to case reports and case series with one nonrandomised study. No high‐quality randomised controlled trials have been published at this stage, precluding a quality systematic review. Guidelines have been published for the use of rFVIIa in non‐obstetric haemorrhage, though to date none are available for PPH. A multidisciplinary group of Australian and New Zealand clinicians from the fields of obstetrics, anaesthesia and haematology, who have both clinical experience in and/or knowledge of rFVIIa was convened by the manufacturer. This group produced an opinion and guideline based on their experience and the published international literature on the use of rFVIIa. This is intended to be used as a guideline and algorithm for the use of rFVIIa, though any use should be tailored to local practice and resources.

Recombinant Activated Factor VII in Obstetric Hemorrhage: Experiences from the Australian and New Zealand Haemostasis Registry

OBJECTIVE: Through the Australian and New Zealand Haemostasis Registry, we report on the Australian and New Zealand experience with recombinant activated factor VII (rFVIIa) in obstetric patients. METHODS: The role of rFVIIa for off-label indications, including trauma, cardiac surgery, and severe postpartum hemorrhage, remains controversial. The Haemostasis Registry established by Monash University in Melbourne, Australia monitors off-label use of rFVIIa across Australia and New Zealand. The purpose of this study was to summarize Registry data for all obstetric hemorrhage patients treated with rFVIIa at participating hospitals between January 2002 and July 2008. The primary outcome measures were reduction or cessation of bleeding (positive therapeutic response), mortality, and hysterectomy rate. RESULTS: During the study period, the Registry received data for 2128 patients. This included 110 cases of administration of rFVIIa in obstetric patients from 38 hospitals, comprising 5% of the total Registry population, 105 of whom were treated for acute hemorrhage. Women received median (interquartile range) individual doses of 92 μg/kg (73–100) of rFVIIa (median total dose 92 μg/kg [58–108]), and 78% of patients received a single dose. The positive response rate to rFVIIa was 76% with 64% responding to the first dose. Ninety-one percent of women were alive at 28 days. Forty-three women (41%) underwent hysterectomy before receiving rFVIIa and, of those remaining, 13 (21%) required hysterectomy after rFVIIa therapy. Two thromboembolic events (1 pulmonary embolism and 1 deep venous thrombosis) and 1 case of hypoxic-ischemic encephalopathy resulting from severe anoxia were reported. CONCLUSIONS: The reported effect of rFVIIa in many, but not all, obstetric cases was positive. There was no mortality as a result of thromboembolic complications. Randomized, controlled trials are required to confirm its safety and efficacy and to assess the possibility that use at an earlier stage in treatment of severe postpartum hemorrhage may avoid the need to resort to postpartum hysterectomy for control of bleeding, thus preserving fertility.

Prediction and prevention of early‐onset pre‐eclampsia: impact of aspirin after first‐trimester screening

To examine the effect of a combination of screening and treatment with low‐dose aspirin on the prevalence of early‐onset pre‐eclampsia (PE).

Tumor necrosis factor α induces a model of preeclampsia in pregnant baboons (Papio hamadryas).

Preeclampsia is a common disease of pregnancy characterised by maternal hypertension and proteinuria. Abnormal placentation in early pregnancy and abnormal cytokine and anti-angiogenic factor expression are thought to contribute to the clinical syndrome of endothelial dysfunction evident in the second half of gestation. The mechanisms underlying both the placental pathology and its translation to the maternal clinical syndrome are not fully understood. A model of preeclampsia manifest by clinically evident endothelial dysfunction (increased blood pressure and proteinuria) was induced by administration of low-dose TNF-α for 2weeks at mid-gestation in pregnant baboons (Papio hamadryas). Blood pressure was monitored continuously and remotely by intra-arterial radiotelemetry. Following TNF-α infusion, there was an increase in systolic and diastolic blood pressure and development of proteinuria in pregnant treated animals, but not in pregnant saline controls nor in non-pregnant TNF-α treated animals. The treated pregnant animals also developed elevated plasma soluble FMS-like tyrosine kinase-1 (sFLT-1) and increased placental mRNA expression of sFLT-1 and soluble endoglin (sEng). These results clearly demonstrate that the cytokine TNF-α can induce the clinical and biochemical features of human preeclampsia. The results identify a link between cytokines, placental dysfunction and endothelial dysfunction resulting in a loss of maternal blood pressure control.

Soluble Flt-1 as a diagnostic marker of pre-eclampsia

Backgound: Serum levels of soluble fms‐like tyrosine kinase (sFlt‐1) increase in pre‐eclampsia (PE).

Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy.

Background Antihypertensive drugs such as clonidine, diazoxide, hydralazine and furosemide are used in the hypertensive disorders of pregnancy to control blood pressure, but it is not clear if they modulate the production of placental or circulating cytokines. Objective To examine the effect of pharmaceutical doses of well known antihypertensive drugs used for blood pressure control on the production of the cytokines interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-α in placental tissue and peripheral blood mononuclear cells (PBMCs) in normal pregnancy. Design Placental biopsies were taken from the decidual surface of placentas after delivery of normal pregnancies (n = 6) and PBMCs were separated from the whole blood of normal term pregnant women (n = 7). Both villous explants and PBMCs were cultured with increasing concentrations of antihypertensive drugs. The dose effect of drugs on the production of placental and circulating cytokines (IL-6, IL-10 and TNF-α) were examined by enzyme-linked immunosorbent assay. Results Placental production of IL-10 was not affected by clonidine, but decreased significantly after incubation of the tissue with diazoxide, hydralazine or furosemide. Production of IL-10 by PBMCs increased significantly: by from 3.4 ± 2.7% [16.3 pg/ml (range 6.1–21.5 pg/ml)] to 24.5 ± 3.3% [30.4 pg/ml (range 16.9–34.8 pg/ml)] with increasing concentrations of clonidine (0.08–1.3 μg/ml), and by 8.8 ± 3.5% [4.1 pg/ml (range 3.0–17.8 pg/ml)] and 17.2 ± 1.9% [22.6 pg/ml (range 13.2–23.2 pg/ml)] with lower doses of hydralazine (6.3 and 12.5 μg/ml) (all P values < 0.05). There was a stepwise reduction in production of TNF-α and IL-6 with increasing doses of diazoxide, hydralazine and furosemide by placentas and PBMCs from these women with normal pregnancies. Conclusion Our data suggest that the antihypertensive drugs clonidine and hydralazine can stimulate production of the circulating anti-inflammatory cytokine IL-10, whereas furosemide and diazoxide inhibit the production of this cytokine and the proinflammatory cytokines TNF-α and IL-6 by placentas and PBMCs.

Effect of hypoxia and exogenous IL-10 on the pro-inflammatory cytokine TNF-α and the anti-angiogenic molecule soluble Flt-1 in placental villous explants

INTRODUCTION The placenta plays a pivotal role in the pathophysiology of preeclampsia. Insufficient trophoblast invasion within the placenta can cause focal regions of ischaemia/hypoxia that, in turn, may stimulate the production of inflammatory cytokines. These cytokines are thought to cause endothelial cell activation and dysfunction, resulting in the clinical signs of preeclampsia. In addition to insufficient trophoblast invasion, the presence of inadequate maternal vasculature remodelling by trophoblasts also leads to changes in angiogenesis that may result from variations in the inflammatory cytokine profile. AIMS This study examined changes in the protein levels of IL-10 (immunoregulatory), TNF-alpha (pro-inflammatory) and sFlt-1 (anti-angiogenic) in normal term placentas under different oxygen tensions. The second aim was to determine if the link between varying levels of the cytokine, IL-10, and the expression/release of TNF-alpha was oxygen dependent, and whether there was a concurrent change in sFlt-1. METHODS Normal term placentas (n=6) were cultured at three different oxygen tensions (2%, 8% or 21%) in the presence or absence of exogenous IL-10. Protein (TNF-alpha and sFlt-1) secretion was measured using commercial ELISA kits, and qRT-PCR was used to examine gene expression. RESULTS Placental IL-10 release was significantly reduced at 2% oxygen when compared to 8% (p=0.045) and 21% (p=0.013). Expression of TNF-alpha and sFlt-1 was not significantly different. Exogenous IL-10 significantly reduced TNF-alpha protein levels only when explants were cultured in 2% oxygen (p=0.05). Soluble Flt-1 protein secretion was unaffected by the addition of IL-10 at any of the oxygen tensions tested. CONCLUSION TNF-alpha release can be inhibited in vitro by IL-10 under hypoxic conditions. However, IL-10 has no affect on sFlt-1 in term placentas, suggesting that these molecules act either via different pathways, or if linked, may be so at different stages of placental development.

Acute Pulmonary Oedema as a Complication of Hypertension During Pregnancy

Objective. To determine rates of and potential causative factors for acute pulmonary oedema (APO) in hypertensive women. Methods. Statistical analysis, including logistic regression, was applied to the individual patient data (IPD) of all hypertensive women who delivered in 2005 at two comparable units. Results. Of 880 cases analysed, there were no women with APO in unit one and 19 women in unit two. The women with APO received larger quantities of intravenous fluids, delivered at earlier gestations, via Caesarean section, following failed induction of labour and had a longer hospital stay. Conclusion. The development of APO in women with hypertension during pregnancy is associated with high levels of intravenous fluid administration.

Role of proteinuria in defining pre-eclampsia: clinical outcomes for women and babies.

1. The presence of proteinuria is not essential to the diagnosis of pre‐eclampsia under many diagnostic consensus statements. The aim of the present study was to assess maternal and perinatal outcomes after proteinuric pre‐eclampsia compared with other non‐proteinuric disease presentations.

A randomised comparison of hydralazine and mini-bolus diazoxide for hypertensive emergencies in pregnancy: The PIVOT trial

Aims:  Diazoxide is one of few available agents for treatment of hypertensive emergencies in pregnancy. From previous studies, there is a question concerning safety after moderate‐dose administration caused episodes of hypotension. Rapid control of severe hypertension is necessary to reduce maternal morbidity, for example, stroke and placental abruption. This study was designed to compare the efficacy of mini‐bolus diazoxide with intravenous (i.v.) hydralazine.