Annemarie Hennessy

The incidence of preeclampsia and eclampsia and associated maternal mortality in Australia from population-linked datasets: 2000-2008

OBJECTIVE To determine the incidence of preeclampsia and eclampsia and associated mortality in Australia between 2000 and 2008. STUDY DESIGN Analysis of statutorily collected datasets of singleton births in New South Wales using International Classification of Disease coding. Analyzed using cross tabulation, logistic regression, and means testing, where appropriate. RESULTS The overall incidence of preeclampsia was 3.3% with a decrease from 4.6% to 2.3%. The overall rate of eclampsia was 8.6/10,000 births or 2.6% of preeclampsia cases, with an increase from 2.3% to 4.2%. The relative risk of eclampsia in preeclamptic women in 2008 was 1.9 (95% confidence interval, 1.28-2.92) when compared with the year 2000. The relative risk of a woman with preeclampsia/eclampsia dying in the first 12 months following birth compared with normotensive women is 5.1 (95% confidence interval, 3.07-8.60). CONCLUSION Falling rates of preeclampsia have not equated to a decline in the incidence of eclampsia. An accurate rate of both preeclampsia and eclampsia is vital considering the considerable contribution that these diseases make to maternal mortality. The identification and treatment of eclampsia should remain a priority in the clinical setting.

Renal connective tissue growth factor correlates with glomerular basement membrane thickness and prospective albuminuria in a non-human primate model of diabetes: possible predictive marker for incipient diabetic nephropathy

UNLABELLED Diabetic renal disease is characterized by accumulation of extracellular matrix, glomerulosclerosis, and tubulointerstitial fibrosis. Connective tissue growth factor (CTGF) is implicated in these changes, as it contributes to new matrix synthesis and is increased in the diabetic kidney. CTGF also inhibits mesangial matrix degradation through up-regulation of the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). In a non-human primate model of diabetes, we determined whether the level of renal CTGF protein before development of albuminuria correlated with renal matrix and TIMP-1 changes and whether renal CTGF predicts progression to albuminuria. METHODS In a group of diabetic (n=9) and control (n=6) baboons after a 5-year duration of diabetes, renal tissue CTGF and TIMP-1 were detected by immunohistochemistry and compared with glomerular basement membrane (GBM) thickness and mesangial volume measurements from electron photomicrographs of renal biopsies. Urinary albumin levels were measured at 5 and 10 years of diabetes. RESULTS GBM thickness, CTGF protein, and TIMP-1 protein were increased after 5 years of diabetes (each P<.05). Tubular fibronectin scores correlated with tubular CTGF scores (r=0.72, P=.002). In diabetic animals, GBM thickness correlated with tubular and total CTGF levels (P=.002 and P=.04, respectively), whereas mesangial cell and total matrix volume correlated with glomerular TIMP-1 (P=.02 and P=.01, respectively). Tubular CTGF scores (P=.008) and GBM thickness (P=.03) at 5 years in diabetes each predicted the degree of albuminuria at 10 years. CONCLUSIONS These results suggest that early increases in renal CTGF protein contribute to incipient diabetic nephropathy and that renal CTGF may have utility as an early marker for progression to dysfunction in the diabetic kidney.

Cardiovascular Risk, Lipids and Pregnancy: Preeclampsia and the Risk of Later Life Cardiovascular Disease

It has been widely thought that the effects of hypertension in pregnancy reversed after delivery and hypertension values returned to their pre-pregnancy level as it was seen as a disease of short duration in otherwise healthy young women. However, recent studies have demonstrated that the principal underlying abnormality, endothelial dysfunction, remains in women who had preeclampsia and that it is this damage that increases the risk of developing cardiovascular disease (CVD) in later life. The contributions of hypertension and dyslipidaemia before and during the pregnancy are also important and contribute to future risk. Serum lipids are complex and change dramatically in pregnancy. In general there is an increase in most plasma lipid components, notably triglycerides, total cholesterol and the major particles of HDL and LDL. Aberrations or exaggerations in this shift (i.e. decrease HDL and a greater increase in LDL) are associated with poor outcomes of pregnancy such as preeclampsia. Long term cardiovascular disease is influenced by preeclampsia and in part potentially by the lipid changes which escalate late in disease. Whether we can influence the risk of preeclampsia by controlling cardiovascular risk factors preceding or during preeclampsia, or cardiovascular disease after preeclampsia is yet to be determined. Ultimately, strategies to control lipid concentrations will only be viable when we understand the safety to the mother at the time of the pregnancy, and to the foetus both immediately and in the very long term. Strategies to control blood pressure are well established in the non-pregnant population, and previous preeclampsia and gestational hypertension should be considered in any cardiovascular risk profile. Whether control of blood pressure in the pregnancy per se is of any longer term benefit is also yet to be determined.

Treatment of sleep disordered breathing reverses low fetal activity levels in preeclampsia.

STUDY OBJECTIVES Preeclampsia affects 5% to 7% of pregnancies, is strongly associated with low birth weight and fetal death, and is accompanied by sleep disordered breathing. We hypothesized that sleep disordered breathing may link preeclampsia with reduced fetal movements (a marker of fetal health), and that treatment of sleep disordered breathing might improve fetal activity during sleep. DESIGN, SETTING, AND PARTICIPANTS First, a method of fetal movement recording was validated against ultrasound in 20 normal third trimester pregnancies. Second, fetal movement was measured overnight with concurrent polysomnography in 20 patients with preeclampsia and 20 control subjects during third trimester. Third, simultaneous polysomnography and fetal monitoring was done in 10 additional patients with preeclampsia during a control night and during a night of nasal CPAP. INTERVENTION Overnight continuous positive airway pressure. MEASUREMENTS AND RESULTS Women with preeclampsia had inspiratory flow limitation and an increased number of oxygen desaturations during sleep (P = 0.008), particularly during REM sleep. Preeclampsia was associated with reduced total fetal movements overnight (319 [SD 32]) versus controls (689 [SD 160], P < 0.0001) and a change in fetal movement patterns. The number of fetal hiccups was also substantially reduced in preeclampsia subjects (P < 0.0001). Continuous positive airway pressure treatment increased the number of fetal movements and hiccups (P < 0.0001 and P = 0.0002, respectively). CONCLUSIONS The effectiveness of continuous positive airway pressure in improving fetal movements suggests a pathogenetic role for sleep disordered breathing in the reduced fetal activity and possibly in the poorer fetal outcomes associated with preeclampsia.

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.

Uteroplacental blood flow and placental vascular endothelial growth factor in normotensive and pre-eclamptic pregnancy

Objective To determine whether placental vascular endothelial growth factor (VEGF) is increased in pre‐eclampsia.

Biochemistry and haematology values for the baboon (Papio hamadryas): the effects of sex, growth, development and age.

Abstract: A retrospective study evaluated the influence of sex and age on plasma biochemistry and haematology parameters in a captive‐bred colony of baboons. Over 1,140 ETDA and heparin blood samples were obtained from 160 clinically normal baboons between the ages of 11 months and 11 years. Data for these blood tests were analysed for the effects of sex, age and sex‐age interactions. Sex, age and sex‐age interactions were detected for many plasma biochemistry and haematological parameters. The reference range values for platelets, white‐blood cells and mean corpuscular volume and plasma chloride, glucose, total protein and iron were higher (P < 0.01) and red blood cell, plasma sodium, potassium, total CO2, creatinine, urea, total bilirubin, albumin, alkaline phosphate, gamma glutamyl transpeptidase and phosphate were lower (P < 0.01) in the female compared to the male population. Sex‐age interactions (P < 0.05) were seen with haemoglobin, white blood cells, haematocrit, mean corpuscular volume, sodium, creatinine, urea, calcium, phosphate, total bilirubin, total protein alkaline phosphatase, the liver enzymes and triglycerides. Plasma alkaline phosphatase was highest (> 800 μ/l) in young juveniles of both sexes; creatinine was higher in older (> 4 years) compared to younger baboons of the same sex (P < 0.05). Plasma cholesterol and triglycerides were greater (P < 0.01) in young baboons compared to older animals.

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).

Preeclampsia is associated with a reduced interleukin-10 production from peripheral blood mononuclear cells.

Problem. This study aims to investigate and compare in vitro, immune cell production of the immunosuppresor cytokine interleukin‐10 (IL‐10) and the proinflammatory cytokine tumor necrosis factor (TNF‐α) between normal pregnancy (NP) and preeclampsia. Methods. Peripheral blood mononuclear cells (PBMC) were isolated from age‐matched patients with preeclampsia and women with a NP (n=3/group) and cultured for 48 hr in the absence and presence of the mitogen phytohaemagluttanin (PHA, 1/100). The concentration of IL‐10 and TNF‐α in the culture medium (CM) was measured by ELISA. Results. Stimulated PBMCs associated with preeclampsia had significantly less IL‐10 in the CM compared to NP (347±39, preeclampsia vs. 689±128, NP; p<0.05) but no difference in TNF‐α. There was no significant difference in IL‐10 or TNF‐α concentration in the CM of unstimulated PBMCs between preeclampsia and NP. Conclusions. These findings suggest that under in vitro stimulated conditions preeclampsia is associated with an abnormality characterized by a diminished ability of peripheral immune cells to produce the immunosupressor cytokine interleukin‐10.

Quantitation of fibroblast activation protein (FAP)-specific protease activity in mouse, baboon and human fluids and organs

The protease fibroblast activation protein (FAP) is a specific marker of activated mesenchymal cells in tumour stroma and fibrotic liver. A specific, reliable FAP enzyme assay has been lacking. FAPs unique and restricted cleavage of the post proline bond was exploited to generate a new specific substrate to quantify FAP enzyme activity. This sensitive assay detected no FAP activity in any tissue or fluid of FAP gene knockout mice, thus confirming assay specificity. Circulating FAP activity was ∼20‐ and 1.3‐fold less in baboon than in mouse and human plasma, respectively. Serum and plasma contained comparable FAP activity. In mice, the highest levels of FAP activity were in uterus, pancreas, submaxillary gland and skin, whereas the lowest levels were in brain, prostate, leukocytes and testis. Baboon organs high in FAP activity included skin, epididymis, bladder, colon, adipose tissue, nerve and tongue. FAP activity was greatly elevated in tumours and associated lymph nodes and in fungal‐infected skin of unhealthy baboons. FAP activity was 14‐ to 18‐fold greater in cirrhotic than in non‐diseased human liver, and circulating FAP activity was almost doubled in alcoholic cirrhosis. Parallel DPP4 measurements concorded with the literature, except for the novel finding of high DPP4 activity in bile. The new FAP enzyme assay is the first to be thoroughly characterised and shows that FAP activity is measurable in most organs and at high levels in some. This new assay is a robust tool for specific quantitation of FAP enzyme activity in both preclinical and clinical samples, particularly liver fibrosis.