Prediction and prevention of venous thrombosis in pregnancy

Venous thromboembolism (VTE) remains the leading cause of maternal mortality. Reports identified further research is required in obese and women post caesarean section (CS). Risk factors for VTE during pregnancy are periodically absent indicating the need for a simple and effective screening tool for pregnancy. Perturbation of the uteroplacental haemostasis has been implicated in placenta mediated pregnancy complications. This thesis had 4 main aims: 1) To investigate anticoagulant effects following a fixed thromboprophylaxis dose in healthy women post elective CS. 2) To evaluate the calibrated automated thrombogram (CAT) assay as a potential predictive tool for thrombosis in pregnancy. 3) To compare the anticoagulant effects of fixed versus weight adjusted thromboprophylaxis dose in morbidly obese pregnant women. 4) To investigate the LMWH effects on human haemostatic gene and antigen expression in placentae and plasma from the uteroplacental , maternal and fetal circulation. Tissue factor pathway inhibitor (TFPI), thrombin antithrombin (TAT), CAT and anti-Xa levels were analysed. Real-time PCR and ELISA were used to quantify mRNA and protein expression of TFPI and TF in placental tissue. In women post CS, anti-Xa levels do not reflect the full anticoagulant effects of LMWH. LMWH thromboprophylaxis in this healthy cohort of patients appears to have a sustained effect in reducing excess thrombin production post elective CS. The results of this study suggest that predicting VTE in pregnant women using CAT assay is not possible at present time. The prothrombotic state in pregnant morbidly obese women was substantially attenuated by weight adjusted but not at fixed LMWH doses. LMWH may be effective in reducing in- vivo thrombin production in the uteroplacental circulation of thrombophilic women. All these results collectively suggest that at appropriate dosage, LMWH is effective in attenuating excess thrombin generation, in low risk pregnant women post caesarean section or moderate to high risk pregnant women who are morbidly obese or tested positive for thrombophilia. The results of the studies provided data to inform evidence-based practice to improve the outcome for pregnant women at risk of thrombosis.

Changes in resting and walking energy expenditure and walking speed during pregnancy in obese women

Background Energy conserving processes reported in undernourished women during pregnancy are a recognised strategy to provide energy required to support fetal development. Women who are obese before conceiving arguably have sufficient fat stores to support the energy demands of pregnancy without the need to provoke energy conserving mechanisms. Objective We tested the hypothesis that obese women would demonstrate behavioural adaptation (i.e. decrease in self-selected walking (SSW) speed) but not metabolic compensation (i.e. decrease in resting metabolic rate (RMR) or metabolic cost of walking) during gestation. Design RMR, SSW speed, metabolic cost of walking, and anthropometry were measured in 23 women (BMI: 33.6 ± 2.5 kg/m2; 31 ± 4 years) at approximately weeks 15 (wk 15) and 30 (wk 30) of gestation. RMR was also measured in two cohorts of non-pregnant controls matched for age, weight and height of the pregnant cohort at wk 15 (N=23) and wk 30 (N=23). Results GWG varied widely (11.3 ± 5.4 kg) and 52% of women gained more weight than is recommended. RMR increased significantly by an average 177 ± 176 kcal/d (11±12%; P<0.0001); however the within-group variability was large. Both the metabolic cost of walking and SSW speed decreased significantly (P<0.01). While RMR increased in >80% of the cohort, the net oxygen cost of walking decreased in the same proportion of women. Conclusions While the increase in RMR was greater than was explained by weight gain, there was evidence of both behavioural and biological compensation in the metabolic cost of walking in obese women during gestation.

Exercise in obese pregnant women: The role of social factors, lifestyle and pregnancy symptoms

Background Physical activity may reduce the risk of adverse maternal outcomes, yet there are very few studies that have examined the correlates of exercise amongst obese women during pregnancy. We examined which relevant sociodemographic, obstetric, and health behaviour variables and pregnancy symptoms were associated with exercise in a small sample of obese pregnant women. Methods This was a secondary analysis using data from an exercise intervention for the prevention of gestational diabetes in obese pregnant women. Using the Pregnancy Physical Activity Questionnaire (PPAQ), 50 obese pregnant women were classified as "Exercisers" if they achieved ≥900 kcal/wk of exercise and "Non-Exercisers" if they did not meet this criterion. Analyses examined which relevant variables were associated with exercise status at 12, 20, 28 and 36 weeks gestation. Results Obese pregnant women with a history of miscarriage; who had children living at home; who had a lower pre-pregnancy weight; reported no nausea and vomiting; and who had no lower back pain, were those women who were most likely to have exercised in early pregnancy. Exercise in late pregnancy was most common among tertiary educated women. Conclusions Offering greater support to women from disadvantaged backgrounds and closely monitoring women who report persistent nausea and vomiting or lower back pain in early pregnancy may be important. The findings may be particularly useful for other interventions aimed at reducing or controlling weight gain in obese pregnant women.

Weight gain and nutritional intake in obese pregnant women : some clues for intervention

Aim:  Maternal obesity is associated with increased risk of adverse outcomes for mothers and offspring. Strategies to better manage maternal obesity are urgently needed; however, there is little evidence to assist the development of nutrition interventions during antenatal care. The present study aimed to assess maternal weight gain and dietary intakes of overweight and obese women participating in an exercise trial. Results will assist the development of interventions for the management of maternal overweight and obesity. Methods:  Fifty overweight and obese pregnant women receiving antenatal care were recruited and provided dietary and weight data at baseline (12 weeks), 28 weeks, 36 weeks gestation and 6 weeks post-partum. Data collected were compared with current nutritional and weight gain recommendations. Associations used Pearson's correlation coefficient, and ANOVA assessed dietary changes over time, P < 0.05. Results:  Mean prepregnancy body mass index was 34.4 ± 6.6 kg/m2. Gestational weight gain was 10.6 ± 6 kg with a wide range (−4.1 to 23.0 kg). 52% of women gained excessive weight (>11.5 kg for overweight and >9 kg for obese women). Gestational weight gain correlated with post-partum weight retention (P < 0.001). Dietary intakes did not change significantly during pregnancy. No women achieved dietary fat or dietary iron recommendations, only 11% achieved adequate dietary folate, and 38% achieved adequate dietary calcium. Very few women achieved recommended food group servings for pregnancy, with 83% consuming excess servings of non-core foods. Conclusion:  Results provide evidence that early intervention and personalised support for obese pregnant women may help achieve individualised goals for maternal weight gain and dietary adequacy, but this needs to be tested in a clinical setting.

Analysis of parameters of haemostasis in pre-eclamptic, normotensive pregnant and non-pregnant women.

Pregnancy is characterized by a state of heightened coagulation, which is exacerbated in pathological conditions such as pre-eclampsia (PET). PET is further associated with abnormal maternal inflammation and increased circulating microparticles (MP); however, a mechanistic link between these pathological features has never been established. It is proposed in this thesis that abnormal maternal inflammation is causally linked to pro-coagulant trophoblast MP shedding via a mechanism mediated by the pro-inflammatory cytokine tumour necrosis factor alpha (TNF), thereby contributing to maternal coagulopathies associated with PET. Using thromboelastography (TEG) and standard laboratory tests, haemostatic function was evaluated in PET and normotensive subjects at delivery and post-partum. Furthermore, the effects of the menstrual cycle and oral contraceptive (OC) use on haemostatic function were assessed in non-pregnant subjects in order to understand their influence on post-partum haemostasis. Plasma TNF and pro-coagulant MP levels were evaluated in the pregnant subjects. Using chorionic villi explants from human term placentas, MPs were quantified after TNF administration. The pro-coagulant potential of placental MPs was evaluated by TEG by spiking whole-blood with medium containing MPs from chorionic villi. TEG identified increased whole-blood coagulability in PET subjects at delivery, demonstrating its increased sensitivity over standard laboratory tests at identifying haemostatic alterations associated with PET. Haemostatic alterations were normalized by six weeks post-partum. TEG also identified cyclic haemostatic variations associated with OC use. Chorionic villi treated with TNF (1 ng/ml) shed significantly more MPs than untreated placentas. MPs from chorionic villi increased the coagulability of whole-blood. Together, results provide evidence supporting the concept that abnormal maternal inflammation is causally linked to the development of maternal coagulopathies in pregnancy complications. Moreover, TEG may be superior to standard laboratory tests in evaluating haemostasis in pregnant and non-pregnant subjects.

No consensus on gestational diabetes mellitus screening regimes in Sweden : pregnancy outcomes in relation to different screening regimes 2011 to 2012, a cross-sectional study

Background: Although associated adverse pregnancy outcomes, no international or Swedish consensus exists that identifies a cut-off value or what screening method to use for definition of gestational diabetes mellitus. This study investigates the following: i) guidelines for screening of GDM; ii) background and risk factors for GDM and selection to OGTT; and iii) pregnancy outcomes in relation to GDM, screening regimes and levels of OGTT 2 hour glucose values. Methods: This cross-sectional and population-based study uses data from the Swedish Maternal Health Care Register (MHCR) (2011 and 2012) combined with guidelines for GDM screening (2011-2012) from each Maternal Health Care Area (MHCA) in Sweden. The sample consisted of 184, 183 women: 88, 140 in 2011 and 96,043 in 2012. Chi-square and two independent samples t-tests were used. Univariate and multivariate logistic regression analyses were performed. Results: Four screening regimes of oral glucose tolerance test (OGTT) (75 g of glucose) were used: A) universal screening with a 2-hour cut-off value of 10.0 mmol/L; B) selective screening with a 2-hour cut-off value of 8.9 mmol/L; C) selective screening with a 2-hour cut-off value of 10.0 mmol/L; and D) selective screening with a 2-hour cut-off value of 12.2 mmol/L. The highest prevalence of GDM (2.9%) was found with a 2-hour cut-off value of 8.9 mmol/L when selective screening was applied. Unemployment and low educational level were associated with an increased risk of GDM. The OR was 4.14 (CI 95%: 3.81-4.50) for GDM in obese women compared to women with BMI <30 kg/m(2). Women with non-Nordic origin presented a more than doubled risk for GDM compared to women with Nordic origin (OR = 2.24; CI 95%: 2.06-2.43). Increasing OGTT values were associated with increasing risks of adverse pregnancy outcomes. Conclusions: There was no consensus regarding screening regimes for GDM from 2011 through 2012 when four different regimes were applied in Sweden. Increasing levels of OGTT 2-hour glucose values were strongly associated with adverse pregnancy outcomes. Based on these findings, we suggest that Sweden adopts the recent recommendations of the International Association of Diabetes and Pregnancy Study Group (IADPSG) concerning the performance of OGTT and the diagnostic criteria for GDM.

Continuity of midwifery care and gestational weight gain in obese women : a randomised controlled trial

Background: The increased prevalence of obesity in pregnant women in Australia and other developed countries is a significant public health concern. Obese women are at increased risk of serious perinatal complications and guidelines recommend weight gain restriction and additional care. There is limited evidence to support the effectiveness of dietary and physical activity lifestyle interventions in preventing adverse perinatal outcomes and new strategies need to be evaluated. The primary aim of this project is to evaluate the effect of continuity of midwifery care on restricting gestational weight gain in obese women to the recommended range. The secondary aims of the study are to assess the impact of continuity of midwifery care on: women’s experience of pregnancy care; women’s satisfaction with care and a range of psychological factors.
Methods/Design: A two arm randomised controlled trial (RCT) will be conducted with primigravid women recruited from maternity services in Victoria, Australia. Participants will be primigravid women, with a BMI≥30 who are less than 17 weeks gestation. Women allocated to the intervention arm will be cared for in a midwifery continuity of care model and receive an informational leaflet on managing weight gain in pregnancy. Women allocated to the control group will receive routine care in addition to the same informational leaflet. Weight gain during pregnancy, standards of care, medical and obstetric information will be extracted from medical records. Data collected at recruitment (self administered survey) and at 36 weeks by postal survey will include sociodemographic information and the use of validated scales to measure secondary outcomes.
Discussion: Continuity of midwifery care models are well aligned with current Victorian, Australian and many international government policies on maternity care. Increasingly, midwifery continuity models of care are being introduced in low risk maternity care, and information on their application in high risk populations is required. There is an identified need to trial alternative antenatal interventions to reduce perinatal risk factors for women who are obese and the findings from this project may have application in other maternity services. In addition this study will inform a larger trial that will focus on birth and postnatal outcomes.

Effect of Type 2 Diabetes Mellitus on the Pharmacokinetics of Metformin in Obese Pregnant Women

Background and Objective The use of metformin throughout gestation by women with polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus (T2DM) significantly reduces the number of first-trimester spontaneous abortions and the rate of occurrence of gestational diabetes and hypertensive syndromes. Metformin is taken up into renal tubular cells by organic cation transport 2 (OCT2) and eliminated unchanged into the urine. The objective of this study was to analyse the influence of T2DM on the pharmacokinetics of metformin in obese pregnant women and in a control group of non-diabetic obese pregnant women with PCOS. Methods Eight non-diabetic obese pregnant women with PCOS and nine obese pregnant women with T2DM taking oral metformin 850 mg every 12 h were evaluated throughout gestation. Serial blood samples were collected over a 12-h period during the third trimester of pregnancy. Steady-state plasma concentrations of metformin were determined by high-performance liquid chromatography with a UV detector. The pharmacokinetic results of the two groups, reported as median and 25th and 75th percentile, were compared statistically using the Mann Whitney test, with the level of significance set at p < 0.05. Results The pharmacokinetic parameters detected for PCOS versus T2DM patients, reported as median, were, respectively: elimination half-life 3.75 versus 4.00 h; time to maximum concentration 2.00 versus 3.00 h; maximum concentration 1.42 versus 1.21 mu g/mL; mean concentration 0.53 versus 0.56 mu g/mL; area under the plasma concentration time curve from time zero to 12 h 6.42 versus 6.73 mu g.h/mL; apparent total oral clearance 105.39 versus 98.38 L/h; apparent volume of distribution after oral administration 550.51 versus 490.98 L; and fluctuation (maximum minimum concentration variation) of 179.56 versus 181.73%. No significant differences in pharmacokinetic parameters were observed between the groups. Conclusion T2DM in the presence of insulin use does not influence the pharmacokinetics of metformin in pregnant patients, demonstrating the absence of a need to increase the dose, and consequently does not influence the OCT2-mediated transport in pregnant women with PCOS.

Health-related quality of life in obese children and adolescents

Objective: This review addresses the effect of overweight and obese weight status on pediatric health-related quality of life (HRQOL). Method: Web of Science, Medline, CINAHL, Cochrane Library, EMBASE, AMED and PubMed were searched for peer-reviewed studies in English reporting HRQOL and weight status in youth (<21 years), published before March 2008. Results: Twenty-eight articles were identified. Regression of HRQOL against body mass index (BMI) using pooled data from 13 studies utilizing the Pediatric Quality of Life Inventory identified an inverse relationship between BMI and pediatric HRQOL (r=−0.7, P=0.008), with impairments in physical and social functioning consistently reported. HRQOL seemed to improve with weight loss, but randomized controlled trials were few and lacked long-term follow-up. Conclusions: Little is known about the factors associated with reduced HRQOL among overweight or obese youth, although gender, age and obesity-related co-morbidities may play a role. Few studies have examined the differences in HRQOL between community and treatment-seeking samples. Pooled regressions suggest pediatric self-reported HRQOL can be predicted from parent proxy reports, although parents of obese youths tend to perceive worse HRQOL than children do about themselves. Thus, future research should include both pediatric and parent proxy perspectives.

Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects

Recombinant glucagon-like peptide-1 (7–36)amide (rGLP-1) was recently shown to cause significant weight loss in type 2 diabetics when administered for 6 weeks as a continuous subcutaneous infusion. The mechanisms responsible for the weight loss are not clarified. In the present study, rGLP-1 was given for 5d by prandial subcutaneous injections (PSI) (76nmol 30min before meals, four times daily; a total of 302·4nmol/24h) or by continuous subcutaneous infusion (CSI) (12·7nmol/h; a total of 304·8nmol/24h). This was performed in nineteen healthy obese subjects (mean age 44·2 (sem 2·5) years; BMI 39·0 (sem 1·2)kg/m2) in a prospective randomised, double-blind, placebo-controlled, cross-over study. Compared with the placebo, rGLP-1 administered as PSI and by CSI generated a 15% reduction in mean food intake per meal (P=0·02) after 5d treatment. A weight loss of 0·55 (sem 0·2) kg (P<0·05) was registered after 5d with PSI of rGLP-1. Gastric emptying rate was reduced during both PSI (P<0·001) and CSI (P<0·05) treatment, but more rapidly and to a greater extent with PSI of rGLP-1. To conclude, a 5d treatment of rGLP-1 at high doses by PSI, but not CSI, promptly slowed gastric emptying as a probable mechanism of action of increased satiety, decreased hunger and, hence, reduced food intake with an ensuing weight loss.

Low fat loss response after medium-term supervised exercise in obese is associated with exercise-induced increase in food reward

Objective: To examine exercise-induced changes in the reward value of food during medium-term supervised exercise in obese individuals. ---------- Subjects/Methods: The study was a 12-week supervised exercise intervention prescribed to expend 500 kcal/day, 5 d/week. 34 sedentary obese males and females were identified as responders (R) or non-responders (NR) to the intervention according to changes in body composition relative to measured energy expended during exercise. Food reward (ratings of liking and wanting, and relative preference by forced choice pairs) for an array of food images was assessed before and after an acute exercise bout. ---------- Results. 20 responders and 14 non-responders were identified. R lost 5.2 kg±2.4 of total fat mass and NR lost 1.7 kg±1.4. After acute exercise, liking for all foods increased in NR compared to no change in R. Furthermore, NR showed an increase in wanting and relative preference for high-fat sweet foods. These differences were independent of 12-weeks regular exercise and weight loss. ---------- Conclusion. Individuals who showed an immediate post-exercise increase in liking and increased wanting and preference for high-fat sweet foods displayed a smaller reduction in fat mass with exercise. For some individuals, exercise increases the reward value of food and diminishes the impact of exercise on fat loss.

The Eat Smart Study : a randomised controlled trial of a reduced carbohydrate versus a low fat diet for weight loss in obese adolescents

Background Despite the recognition of obesity in young people as a key health issue, there is limited evidence to inform health professionals regarding the most appropriate treatment options. The Eat Smart study aims to contribute to the knowledge base of effective dietary strategies for the clinical management of the obese adolescent and examine the cardiometablic effects of a reduced carbohydrate diet versus a low fat diet. Methods and design Eat Smart is a randomised controlled trial and aims to recruit 100 adolescents over a 2½ year period. Families will be invited to participate following referral by their health professional who has recommended weight management. Participants will be overweight as defined by a body mass index (BMI) greater than the 90th percentile, using CDC 2000 growth charts. An accredited 6-week psychological life skills program ‘FRIENDS for Life’, which is designed to provide behaviour change and coping skills will be undertaken prior to volunteers being randomised to group. The intervention arms include a structured reduced carbohydrate or a structured low fat dietary program based on an individualised energy prescription. The intervention will involve a series of dietetic appointments over 24 weeks. The control group will commence the dietary program of their choice after a 12 week period. Outcome measures will be assessed at baseline, week 12 and week 24. The primary outcome measure will be change in BMI z-score. A range of secondary outcome measures including body composition, lipid fractions, inflammatory markers, social and psychological measures will be measured. Discussion The chronic and difficult nature of treating the obese adolescent is increasingly recognised by clinicians and has highlighted the need for research aimed at providing effective intervention strategies, particularly for use in the tertiary setting. A structured reduced carbohydrate approach may provide a dietary pattern that some families will find more sustainable and effective than the conventional low fat dietary approach currently advocated. This study aims to investigate the acceptability and effectiveness of a structured reduced dietary carbohydrate intervention and will compare the outcomes of this approach with a structured low fat eating plan. Trial Registration: The protocol for this study is registered with the International Clinical Trials Registry (ISRCTN49438757).