Pregnancy complications associated with placental development affect approximately one third of all human pregnancies. Genome health is essential for placental and fetal development, as DNA damage can lead to pregnancy loss and developmental defects. During this developmental phase rapid DNA replication provides an increased opportunity for genome and epigenome damage to occur[1]. Maternal nutrition is one of the principal environmental factors supporting the high rate of cell proliferation and differentiation. Folate functions in one-carbon metabolism and regulates DNA synthesis, DNA repair and gene expression[1]. Deficiencies or defects in gene-nutrient interactions associated with one-carbon metabolism can lead to inhibition of cell division, cell cycle delay and an excessive apoptotic or necrotic cell death rate [2], which may affect placentation. This study is the first to investigate the association between genomic damage biomarkers in late pregnancy complications associated with uteroplacental insufficiency (UPI) including preeclampsia and intrauterine growth restriction (IUGR). The results indicate that genome damage in the form of micronucleated cells in peripheral blood lymphocytes at 20 weeks gestation is significantly increased in women at risk of developing an adverse pregnancy outcome. The observed OR for the high micronuclei frequency may be the highest observed for any biomarker selected in relation to risk of pregnancy complications to date (15.6 – 33.0). In addition, reduced apoptosis was observed in association with increased micronuclei, suggesting that the cells may have escaped specific cell-cycle checkpoints allowing a cell with DNA damage to proceed through mitosis. This study demonstrated that an increase in plasma homocysteine concentration at 20 weeks gestation is associated prospectively with the subsequent development of UPI, indicating a causal relationship. The MTR 2756 GG genotype was significantly associated with increased plasma homocysteine concentration and UPI. Furthermore, the MTHFD1 1958 single nucleotide polymorphism was associated with increased risk for IUGR. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1309296 / Thesis (Ph.D.) -- School of Paediatrics and Reproductive Health, 2007

Pregnancy in women with hemoglobinopathy has been associated with an increased risk of adverse pregnancy outcomes. We conducted a historical cohort study using Discharge Abstract Database for the fiscal year 1991-1992 through 2007-2008. We estimated the frequency of pregnant women with hemoglobinopathy and examined their associations with adverse pregnancy outcomes. Women with sickle cell disease are more likely to develop pre-eclampsia and preterm labor, and to undergo cesarean delivery than women with nutritional deficiency anemia, suggesting that there are other mechanisms beyond anemia that may be responsible for an increased risk of adverse pregnancy outcomes. The data suggested a synergistic effect of hemoglobinopathy and pre-eclampsia on preterm labor and cesarean delivery. Prediction models for pre-eclampsia, preterm labor and cesarean delivery were created and internally validated for women with hemoglobinopathy, with satisfactory discrimination and calibration.

Background: Pre-eclampsia (PET) is one of the major causes of maternal and neonatal morbidity and mortality1. Misclassification of PET can lead to biased or erroneous results in epidemiologic studies resulting in false conclusions. Objectives: The objectives of this thesis are to determine the validity of PET diagnosis in pregnant women in administrative database using the ICD-10-CA codes, to explore the nature of misclassification, and to estimate whether misclassification of PET diagnosis in administrative database may result in biased conclusions. Methods: Pregnant women who participated in the Ottawa and Kingston (OaK) Birth Cohort study and delivered in the Ottawa Hospital were included in the study. All cases with hypertensive disorder of pregnancy in the study population were adjudicated to confirm diagnosis of PET. This adjudicated dataset was used as a reference standard. The PET incidence in hospital discharge database was compared with PET incidence calculated from the reference standard database. Results: 2887 of the requested charts were available for review. The PET incidence was much lower in administrative database (1.47%) than in the OaK Birth Cohort Study (3.6%). The results of the study demonstrated that hospital discharge database via ICD-10-CA was not very sensitive to determine incidence of PET since sensitivity of ICD-10-CA diagnostic codes for PET was low (35.92% with 95% Confidence Intervals (CI): 26.7; 45.9) but specificity, PPV, and NPV were high. The majority of misclassified cases belonged to the category (according to the proposed classification) “PET pregnancies coded with incorrect ICD-10-CA code” (78.88%) followed by the category “Pregnancies affected by PET coded as normal” (14.08%). Conclusion: Using hospital discharge database and ICD-10-CA coding to determine incidence of PET in certain settings may yield low sensitivity. Researchers should validate the results when using the hospital discharge database for PET research to ensure that the findings based on analyses of such data demonstrate what they claimed to demonstrate.

Pregnancy in women with hemoglobinopathy has been associated with an increased risk of adverse pregnancy outcomes. We conducted a historical cohort study using Discharge Abstract Database for the fiscal year 1991-1992 through 2007-2008. We estimated the frequency of pregnant women with hemoglobinopathy and examined their associations with adverse pregnancy outcomes. Women with sickle cell disease are more likely to develop pre-eclampsia and preterm labor, and to undergo cesarean delivery than women with nutritional deficiency anemia, suggesting that there are other mechanisms beyond anemia that may be responsible for an increased risk of adverse pregnancy outcomes. The data suggested a synergistic effect of hemoglobinopathy and pre-eclampsia on preterm labor and cesarean delivery. Prediction models for pre-eclampsia, preterm labor and cesarean delivery were created and internally validated for women with hemoglobinopathy, with satisfactory discrimination and calibration.

Angiotensinogen is a blood protein that plays a critical role in the regulation of blood pressure in the body. This protein exists in two forms, oxidised and reduced, determined by the presence or absence of a disulfide bridge between Cys 18 and Cys 138. The ratio of oxidised to reduced angiotensinogen is 60:40 in the blood of healthy individuals - an equilibrium that is disrupted in women who develop pre-eclampsia, leading to a higher proportion of oxidised angiotensinogen in the blood. Pre-eclampsia, one of the leading causes of premature births, is a severe and potentially fatal pregnancy condition characterised by the sudden onset of symptoms such as high blood pressure and proteinuria typically during the third trimester. This condition is responsible for an estimated 550,000 deaths globally each year, and with no available treatment or cure other than early delivery of the child, there is a desperate need for a reliable and predictive diagnostic test for this condition. Can we use angiotensinogen as a biomarker for the early diagnosis of pre-eclampsia? Being able to distinguish between reduced and oxidised angiotensinogen and determine the relative amounts of each in blood samples would be of a huge diagnostic value for this condition. This thesis outlines the expression and purification of recombinant human angiotensinogen in Escherichia coli, and the development of an antibody-based SPR assay for angiotensinogen that was subsequently used to probe whether reduced and oxidised angiotensinogen can be distinguished experimentally. The assay developed was sensitive and reproducible, and demonstrated that the reduced and oxidised forms can be distinguished experimentally. The antibody bound the two forms with differential affinity, due to differences in both the association and dissociation rates of the two forms with the monoclonal antibody. Finally, in an attempt to further elucidate the differences between the two redox states of angiotensinogen, molecular dynamic simulations were carried out on angiotensinogen in the presence or absence of the disulfide bond between Cys 18 and Cys 138. These simulations revealed some quite striking differences in the dynamics between the two forms. Reduced angiotensinogen was found to be more dynamic in regions critical for binding to renin, providing a possible explanation for the reported differential affinity that renin displays for the two forms.1 Thus, reduced and oxidised angiotensinogen show some quite distinct differences and can be distinguished in an SPR-based assay, highlighting their potential for use as a biomarker in a diagnostic bioassay.

Pregnancy in women with hemoglobinopathy has been associated with an increased risk of adverse pregnancy outcomes. We conducted a historical cohort study using Discharge Abstract Database for the fiscal year 1991-1992 through 2007-2008. We estimated the frequency of pregnant women with hemoglobinopathy and examined their associations with adverse pregnancy outcomes. Women with sickle cell disease are more likely to develop pre-eclampsia and preterm labor, and to undergo cesarean delivery than women with nutritional deficiency anemia, suggesting that there are other mechanisms beyond anemia that may be responsible for an increased risk of adverse pregnancy outcomes. The data suggested a synergistic effect of hemoglobinopathy and pre-eclampsia on preterm labor and cesarean delivery. Prediction models for pre-eclampsia, preterm labor and cesarean delivery were created and internally validated for women with hemoglobinopathy, with satisfactory discrimination and calibration.

Pregnancy complications associated with placental development affect approximately one third of all human pregnancies. Genome health is essential for placental and fetal development, as DNA damage can lead to pregnancy loss and developmental defects. During this developmental phase rapid DNA replication provides an increased opportunity for genome and epigenome damage to occur[1]. Maternal nutrition is one of the principal environmental factors supporting the high rate of cell proliferation and differentiation. Folate functions in one-carbon metabolism and regulates DNA synthesis, DNA repair and gene expression[1]. Deficiencies or defects in gene-nutrient interactions associated with one-carbon metabolism can lead to inhibition of cell division, cell cycle delay and an excessive apoptotic or necrotic cell death rate [2], which may affect placentation. This study is the first to investigate the association between genomic damage biomarkers in late pregnancy complications associated with uteroplacental insufficiency (UPI) including preeclampsia and intrauterine growth restriction (IUGR). The results indicate that genome damage in the form of micronucleated cells in peripheral blood lymphocytes at 20 weeks gestation is significantly increased in women at risk of developing an adverse pregnancy outcome. The observed OR for the high micronuclei frequency may be the highest observed for any biomarker selected in relation to risk of pregnancy complications to date (15.6 – 33.0). In addition, reduced apoptosis was observed in association with increased micronuclei, suggesting that the cells may have escaped specific cell-cycle checkpoints allowing a cell with DNA damage to proceed through mitosis. This study demonstrated that an increase in plasma homocysteine concentration at 20 weeks gestation is associated prospectively with the subsequent development of UPI, indicating a causal relationship. The MTR 2756 GG genotype was significantly associated with increased plasma homocysteine concentration and UPI. Furthermore, the MTHFD1 1958 single nucleotide polymorphism was associated with increased risk for IUGR. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1309296 / Thesis (Ph.D.) -- School of Paediatrics and Reproductive Health, 2007

Diss. (sammanfattning) Linköping : Linköpings universitet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 99-120).