Abstract The incidence of pre-eclampsia (PE) is 2–7% in different populations and in the worst cases PE may threaten the survival of both mother and newborn; its pathogenesis is not resolved. Field literature today considers PE an angiogenic disorder. Coordinated vascularization is essential for placental development. We wanted to find novel factors in the etiology of PE, and focused our attention on angiogenesis, inherited thrombophilia and folate-homocysteine metabolism. Homocysteine inhibits endothelial cell proliferation, which is closely related to angiogenesis. We performed gene expression profiling of placental tissue using microarray chips, studied the prevalence of factor V Leiden (FVL), prothrombin (F5) G20210A and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in patients with severe pregnancy complications and normal controls, compared the expression of the placental adiponectin, leptin and their receptor genes and the relationship of each to trophoblast apoptosis and further, studied the effect of folic acid fortified mineral water on plasma homocysteine concentration during pregnancy. Gene expression profiling revealed downregulation of nine and upregulation of four genes. Interestingly, in one PE patient with cord compression during delivery the profile resembled that observed in normals. The expression level of the leptin and the adiponectin receptor 1 (ADIPOR1) genes was significantly higher in PE. No other significant expression changes were observed. The rate of apoptosis was higher in patients with PE. The FVL prevalence was 9.5%, in PE cases and 1.8% in the controls; a difference of 7.7%, (95% CI 2.0–13.4%). No statistical difference was found in other polymorphisms.. Maternal serum folate concentration increased in our intervention group, but decreased in the control group (p < 0.05). The plasma homocysteine concentrations decreased more in the intervention group (p < 0.001). The expression of angiogenesis-related placental genes can be altered in PE and cord compression cases. The activity of adipocytokine genes in PE may mean that they have a role in placental angiogenesis and apoptosis. Women with FVL may have an increased risk of PE. Fortified mineral water will help us to ensure that especially pregnant women achieve adequate folate intake.

Preeclampsia and eclampsia are among the most common causes of maternal and fetal mortality and morbidity worldwide. There are no reliable means to predict eclampsia or cerebral edema in women with preeclampsia and knowledge of the brain involvement in preeclampsia is still limited. S100B and neuron specific enolase (NSE) are two cerebral biomarkers of glial- and neuronal origin respectively. They are used as predictors for neurological outcome after traumatic brain injuries and cardiac arrest but have not yet been investigated in preeclampsia. This thesis is based on one longitudinal cohort study of pregnant women (n=469, Paper I and III), one cross sectional study of women with preeclampsia and women with normal pregnancies (n=53 and 58 respectively, Paper II and IV) and one experimental animal study of eclampsia (Paper V). In Paper I and III, plasma concentrations of S100B and NSE were investigated throughout pregnancy in women developing preeclampsia (n=16) and in women with normal pregnancies (n=36) in a nested case control study. Plasma concentrations were increased in women developing preeclampsia in gestational week 33 and 37 for S100B and in gestational week 37 for NSE compared to women with normal pregnancies. In Paper II and IV, increased plasma concentrations of S100B and NSE were confirmed among women with preeclampsia compared to women with normal pregnancies. Furthermore, increased plasma concentrations of S100B correlated to visual disturbances among women with preeclampsia (Paper II) and plasma concentrations of S100B and NSE remained increased among women with preeclampsia one year after delivery (Paper IV). In Paper V, an experimental rat model of preeclampsia and eclampsia demonstrated increased serum concentrations of S100B after seizures in normal pregnancy (n=5) and a tendency towards increased plasma concentrations of S100B in preeclampsia (n=5) compared to normal pregnancy (n=5) without seizures. Furthermore, after seizures, animals with magnesium sulphate treatment demonstrated increased serum concentrations of S100B and NSE compared to no treatment. In conclusion; plasma concentrations of S100B and NSE are increased in preeclampsia during late pregnancy and postpartum and S100B correlates to visual disturbances in women with preeclampsia. The findings are partly confirmed in an animal model of eclampsia.

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.

Pre-eclampsia (PE) is a serious disease affecting approximately 5% of pregnancies per annum. The disease etiology is complex but its origin lies in abnormal placental development and function. PE is associated with inflammation, increased nitrative stress and abnormal renewal of syncytiotrophoblast (STB), the transporting epithelium of the placenta. STB is renewed by cytotrophoblasts (CTBs) that proliferate, differentiate and fuse with STB and this is balanced by apoptosis. The amino acid taurine facilitates proliferation, differentiation and apoptosis in non-placental tissues. Taurine is also cytoprotective, protecting cells from damage by inflammatory cytokines. Taurine is transported from maternal blood into STB by the amino acid transporter TauT. In isolated STB membranes, TauT activity is inhibited by agents that nitrate tyrosine residues. This thesis tested the hypothesis that STB TauT activity is down-regulated in PE due to post-translational modification of TauT through tyrosine nitration which lowers intracellular taurine and contributes to altered STB renewal. Placentas were collected from normal pregnancy (NP) and PE (blood pressure >140/90mmHg after 20 weeks gestation in previously normotensive women plus proteinuria >300 mg/L in a 24-hour collection). STB TauT activity, measured as Na+-dependent uptake of 3H-taurine into placental villous fragments, was significantly lower in PE (n=24) compared to NP (n=44). Western blotting of membrane enriched homogenates showed that TauT protein expression (normalised to β-actin) was significantly higher in placentas from PE (n=8) compared to NP (n=9). The presence of nitrotyrosine residues (marker of nitrative stress) in placentas of women with PE and NP was assessed by immunohistochemistry (IHC). The intensity of STB nitrotyrosine staining was greater in PE placentas that had reduced TauT activity (n=8) than in NP (n=7). To determine the effect of nitrative stress on TauT activity and STB renewal, placental villous explants from NP were cultured (7 days; n=6) and treated with SIN-1 (1mM; days 5,6) to induce nitrative stress. STB nitrotyrosine (IHC) and TauT activity (3H-taurine uptake) was determined on day 7 and STB renewal was assessed by IHC for apoptosis (M30), proliferation (dual staining for Ki67 and the CTB marker E-cadherin) and STB integrity (cytokeratin 7). SIN-1 increased STB nitrotyrosine staining intensity compared to controls, confirming induction of nitrative stress. SIN-1 reduced STB TauT activity, increased apoptosis, reduced CTB proliferation and altered STB regeneration compared to control. To determine the effect of reducing intracellular taurine on STB renewal, villous explants were cultured for 7 days with 2.5mM β-alanine to competitively inhibit taurine uptake (n=6). At day 7, intracellular taurine, measured as the steady-state accumulation of 3H-taurine, was 15% of normal. STB turnover was assessed at day 7 as described above. β-alanine significantly increased apoptosis and altered STB regeneration compared to controls. Following statistical analysis all p <0.05.In conclusion, STB TauT activity was lower, and protein expression higher, in PE compared to NP. STB nitrotyrosine was elevated in PE and nitrative stress inhibited STB TauT activity and disrupted STB renewal in vitro. Reducing intracellular taurine also disrupted STB renewal in vitro. Overall the data support the hypothesis that post-translational modification of TauT by nitration inhibits TauT activity in PE. This reduces intracellular taurine which contributes to abnormal renewal of STB. Further work is needed (a) to confirm that TauT is nitrated in PE and that reduced STB TauT activity lowers intracellular taurine and reduces taurine delivery to the fetus and (b) to determine the mechanism/s by which taurine regulates CTB apoptosis and facilitates renewal of STB.

Objetivo: Determinar la asociación entre el hiperinsulinismo (HI) y embarazo en mujeres con síndrome de ovario poliquístico (SOP). Diseño: Revisión Sistemática y Meta-Análisis de estudios observacionales que evaluaron la asociación entre hiperinsulinismo y desenlaces obstétricos. Se realizó la búsqueda de la literatura a través de las bases PubMed-MEDLINE, Web of Science, Embase, Scopus y Cochrane hasta junio del 2015. Paciente(s): Mujeres en edad reproductiva con síndrome de ovario poliquístico. Principales medidas del resultado: El desenlace primario fue embarazo; los desenlaces secundarios fueron aborto espontaneo, diabetes gestacional y preeclampsia. Para el análisis del estudio se utilizó el modelo de efectos aleatorios. Resultados: Encontramos siete cohortes prospectivas y cuatro estudios de casos y control (n=711). La proporción de embarazo en las mujeres con hiperinsulinemia fue significativamente menor que en las mujeres sin hiperinsulinemia (45/213 [21.1%] vs 114/273 [41.8%], OR 0.36, IC 95% 0.21-0.62, P<0.001). No hubo diferencia en porcentaje de abortos entre aquellas con hiperinsulinemia y aquellas sin hiperinsulinemia (9/100 [9.0%] vs 15/147 [10.2%], OR 0.90, IC 95% 0.36-2.22, P˃0.001). La información fue escasa respecto a los efectos de en diabetes gestacional y pre-eclampsia. Conclusiones: Existe asociación significativa e inversa entre hiperinsulinismo y embarazo en mujeres con síndrome de ovario poliquístico. Asimismo, no se encontró diferencias entre pacientes SOP con HI y pacientes SOP sin HI respecto al riesgo de aborto. Por otro lado, no hubo información suficiente para analizar los desenlaces diabetes gestacional y preeclampsia. / OBJECTIVE: To determine the association between hyperinsulinism (HI) and pregnancy in women with polycystic ovarian syndrome (PCOS). PATTERN: Systematic Review and Meta-Analysis of observational studies that evaluated the association between hyperinsulinism and obstetric outcomes. We searched the literature through the databases of PubMed-MEDLINE, Web of Science, Embase, Scopus and Cochrane databases until June 2015. PATIENT(s): Women on reproductive age with polycystic ovarian syndrome. MAIN EFFECTS OF RESULTS: The primary outcome was pregnancy; The secondary outcomes were miscarriage, gestational diabetes and preeclampsia. For the analysis of the study we used the random effects model. RESULTS: We found 7 prospective cohorts and 4 case-control studies (n = 711). The percentage of pregnancy in women with hyperinsulinemia was significantly lower than in women without hyperinsulinemia (45/213 [21.1%] vs 114/273 [41.8%], or 0.36, 95% ci 0.21-0.62, p <0.001). There was no difference in the percentage of miscarriages between women with hyperinsulinemia and women without hyperinsulinemia (9/100 [9.0%] vs 15/147 [10.2%], or 0.90, 95% ci 0.36-2.22, p0.001). The information was scarce regarding the effects of gestational diabetes and pre-eclampsia. Conclusions: There is a significant and inverse association between hyperinsulinism and pregnancy in women with PCOS. Likewise, we do not found differences between PCOS patients with HI and PCOS patients without HI regarding the risk of miscarriage.On the other hand, there was not enough information to analyze the results of gestational diabetes and preeclampsia. / Tesis

Theses ( MPH.) -- University of Limpopo, 2021 / Background: Maternal mortality is a significant public health problem worldwide, and is a vital indicator of the functioning of a health system. The South African maternal mortality ratio is higher than other countries with same economic growth, despite people having free access to maternal health. How to develop relevant policies and programmes to reduce maternal mortality factors contributing to maternal mortality was investigated. Aims of the Study: To investigate the factors contributing to maternal mortality in public health institutions in the Sekhukhune District, Limpopo Province, South Africa. Methods: A quantitative, retrospective study was undertaken where 138 medical records of maternal mortality cases reported between 2013 to 2017 were reviewed. A simple random sampling method was used to select files that met the selection criteria from seven hospitals in the Sekhukhune District, Information was collected on maternal demographics and health service-related characteristics, including age, marital status, parity, antenatal care utilisation of services and delivery type. Inferential data were analysed using the student t-test and SPSS version 25. Results: The mean age of the women involved in this study was 30 years, with a standard deviation of 5.7. All the women who participated in the study were black African. The majority of maternal mortality occurred in hospital. The women in the majority of maternal mortality cases were unemployed, at 93.5%, while most of the maternal mortality cases involved single women (71%).The women involved in these maternal mortality cases booked their ANC care and the major health provider was a professional nurse (58.0%), while 57.2% of the participants attended their ANC at primary healthcare facilities. Most of the maternal deaths occurred after delivery (58.7%) and, in most deliveries, the Partogram was not used (66%). HIV testing occurred in 99% of the maternal mortality cases. The causes of maternal mortality were both direct (71.0%) and indirect (23.9%) causes. The leading cause of maternal mortality was direct haemorrhage (33%), followed by eclampsia (27%) and infection (16%). The leading indirect cause was respiratory causes (22%) and retro viral disease (RVD) (9%). The personal factor that contributed most to maternal mortality was delay in seeking help (62%). v Conclusion and Recommendations: The personal factor, delay in seeking medical help by the women, contributed to maternal mortality and it was further concluded that the majority of maternal mortality cases did not occur as a result of any complications in ANC and delivery. It is recommended that the training of healthcare providers in the utilisation of the Partogram be implemented to improve skills in the management of haemorrhage and eclampsia. Furthermore, the management of complications needs to be strengthened through a multi-sectorial approach. / SAMRC

Objective: To evaluate the association between preeclampsia (PE) and eclampsia (E) on subsequent metabolic and biochemical outcomes. Methods: Systematic review and meta-analysis of observational studies. We searched five engines until November 2018 for studies evaluating the effects of PE/E on metabolic and biochemical outcomes after delivery. PE was defined as presence of hypertension and proteinuria at >20 weeks of pregnancy; controls did not have PE/E. Primary outcomes were blood pressure (BP), body mass index (BMI), metabolic syndrome (MetS), blood lipids and glucose levels. Random effects models were used for meta-analyses, and effects reported as risk difference (RD) or mean difference (MD) and their 95% confidence interval (CI). Subgroup analyses by time of follow up, publication year, and confounder adjustment were performed. Results: We evaluated 41 cohorts including 3300 PE/E and 13,967 normotensive controls. Women were followed up from 3 months after delivery up to 32 years postpartum. In comparison to controls, PE/E significantly increased systolic BP (MD = 8.3 mmHg, 95%CI 6.8 to 9.7), diastolic BP (MD = 6.8 mmHg, 95%CI 5.6 to 8.0), BMI (MD = 2.0 kg/m2; 95%CI 1.6 to 2.4), waist (MD = 4.3 cm, 95%CI 3.1 to 5.5), waist-to-hip ratio (MD = 0.02, 95%CI 0.01 to 0.03), weight (MD = 5.1 kg, 95%CI 2.2 to 7.9), total cholesterol (MD = 4.6 mg/dL, CI 1.5 to 7.7), LDL (MD = 4.6 mg/dL; 95%CI 0.2 to 8.9), triglycerides (MD = 7.7 mg/dL, 95%CI 3.6 to 11.7), glucose (MD = 2.6 mg/dL, 95%CI 1.2 to 4.0), insulin (MD = 19.1 pmol/L, 95%CI 11.9 to 26.2), HOMA-IR index (MD = 0.7, 95%CI 0.2 to 1.2), C reactive protein (MD = 0.05 mg/dL, 95%CI 0.01 to 0.09), and the risks of hypertension (RD = 0.24, 95%CI 0.15 to 0.33) and MetS (RD = 0.11, 95%CI 0.08 to 0.15). Also, PE/E reduced HDL levels (MD = –2.15 mg/dL, 95%CI –3.46 to −0.85). Heterogeneity of effects was high for most outcomes. Risk of bias was moderate across studies. Subgroup analyses showed similar effects as main analyses. Conclusion: Women who had PE/E have worse metabolic and biochemical profile than those without PE/E in an intermediate to long term follow up period. © / Revisión por pares

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 4 uppsatser. Även tryckt utgåva.

Student Number : 9402058P - M Med Research Report - School of Clinical Medicine - Faculty of Health Sciences / Objective In view of recent suggestions that HIV infection may protect against pre-eclampsia, this study was done to estimate whether untreated HIV positive pregnant women have a lower rate of preeclampsia-eclampsia than HIV negative women. Methods Subjects for this study were pregnant women from Soweto, South Africa, who gave birth from March to December 2002 at midwife-run clinics or at the Chris Hani Baragwanath Hospital, and in whom the HIV status was known. A sample size calculation indicated that 2588 subjects would be required to show statistical significance at P<0.05 with a power of 80% for a reduction in the rate of preeclampsia from 8% to 5% with HIV seropositivity, assuming an HIV seroprevalence rate of 30%. Data collection was by record review from randomly selected patient files and birth registers. Results In the total sample of 2600 women, 1797 gave birth at the hospital and 803 at the midwife-run clinics. The HIV seroprevalence rate was 27.1%. Hypertension was found in 17.3% of women, with 5.3% having preeclampsia-eclampsia. The rates of preeclampsia-eclampsia were 5.2% in HIV negative and 5.7% in HIV positive women (P=0.61). CD4 count results were available for only 13 women (0.5%). Conclusion HIV seropositivity was not associated with any reduction in the risk of developing preeclampsia-eclampsia.