Fetal overgrowth is associated with adverse outcomes for offspring and with maternal obesity. Results from a systematic review and meta-analysis showed that maternal obesity is associated with fetal overgrowth, defined as birthweight ≥4000g (OR 2.17, 95% CI 1.92, 2.45), birthweight ≥4500g (OR 2.77, 95% CI 2.22, 3.45) and birthweight ≥90%ile for gestational age (OR 2.42, 95% CI 2.16, 2.72). A retrospective cohort study revealed that mothers whose infants are macrosomic are more likely to require induction of labour (OR 1.42, 95% CI 1.10-1.98) and delivery by Cesarean section (OR 1.45, 95% CI 1.04-2.01), particularly for maternal indications (OR 3.7, 95% CI 1.47-9.34), if they are obese. Infants from these pregnancies are significantly more likely to require neonatal resuscitation in the form of free flow oxygen (OR 1.57, 95% CI 1.03, 2.42) than macrosomic infants of non-obese mothers. Thus, co-existing maternal obesity and macrosomia increases the risk of adverse pregnancy outcomes.

Background Air pollution exposure has been shown to have adverse effects on several health outcomes, and numerous studies have reported associations with cardiovascular morbidity, respiratory disease, and mortality. Over the last decade, an increasing number of studies have investigated possible associations with pregnancy outcomes, including preterm delivery. High levels of vehicle exhaust in residential neighborhoods have been associated with respiratory effects, including childhood asthma, and preterm birth is also associated with childhood asthma. The first aim of this thesis was to investigate possible associations between air pollution exposure and pregnancy outcomes – primarily preterm delivery but also small for gestational age (SGA) and pre-eclampsia – in a large Swedish population (Papers I–III). The second aim was to study any association between exposure to high levels of vehicle exhaust during pregnancy and infancy and prescribed asthma medication in childhood (Paper IV). Methods The study cohorts were constructed by matching other individual data to the Swedish Medical Birth Register. In the first two studies, air pollution data from monitoring stations were used, and in the third and fourth studies traffic intensity and dispersion model data were used.Preterm delivery was defined as giving birth before 37 weeks of gestation. SGA was defined as having a birth weight below the 10th percentile for a given duration of gestation. Pre-eclampsia was defined as having any of the ICD-10 diagnosis codes O11 (pre-existing hypertension with pre-eclampsia), O13 (gestational hypertension without significant proteinuria), O14 (gestational hypertension with significant proteinuria), or O15 (eclampsia). Childhood asthma medication was defined as having been prescribed asthma medication between the ages of five and six years. Results We observed an association between ozone exposure during the first trimester and preterm delivery. First trimester ozone exposure was also associated with pre-eclampsia. The modeled concentration of nitrogen oxides at the home address was associated with pre-eclampsia, but critical time windows were not possible to investigate due to high correlations between time windows. We did not observe any association between air pollution exposure and SGA. High levels of vehicle exhaust at the home address, estimated by nitrogen oxides and traffic intensity, were associated with a lower risk of asthma medication. Conclusion Air pollution exposure during pregnancy was associated with preterm delivery and pre-eclampsia. We did not observe any association between air pollution levels and intrauterine growth measured as SGA. No harmful effect of air pollution exposure during pregnancy or infancy on the risk of being prescribed asthma medication between five and six years of age was observed.

Fetal overgrowth is associated with adverse outcomes for offspring and with maternal obesity. Results from a systematic review and meta-analysis showed that maternal obesity is associated with fetal overgrowth, defined as birthweight ≥4000g (OR 2.17, 95% CI 1.92, 2.45), birthweight ≥4500g (OR 2.77, 95% CI 2.22, 3.45) and birthweight ≥90%ile for gestational age (OR 2.42, 95% CI 2.16, 2.72). A retrospective cohort study revealed that mothers whose infants are macrosomic are more likely to require induction of labour (OR 1.42, 95% CI 1.10-1.98) and delivery by Cesarean section (OR 1.45, 95% CI 1.04-2.01), particularly for maternal indications (OR 3.7, 95% CI 1.47-9.34), if they are obese. Infants from these pregnancies are significantly more likely to require neonatal resuscitation in the form of free flow oxygen (OR 1.57, 95% CI 1.03, 2.42) than macrosomic infants of non-obese mothers. Thus, co-existing maternal obesity and macrosomia increases the risk of adverse pregnancy outcomes.

Fetal overgrowth is associated with adverse outcomes for offspring and with maternal obesity. Results from a systematic review and meta-analysis showed that maternal obesity is associated with fetal overgrowth, defined as birthweight ≥4000g (OR 2.17, 95% CI 1.92, 2.45), birthweight ≥4500g (OR 2.77, 95% CI 2.22, 3.45) and birthweight ≥90%ile for gestational age (OR 2.42, 95% CI 2.16, 2.72). A retrospective cohort study revealed that mothers whose infants are macrosomic are more likely to require induction of labour (OR 1.42, 95% CI 1.10-1.98) and delivery by Cesarean section (OR 1.45, 95% CI 1.04-2.01), particularly for maternal indications (OR 3.7, 95% CI 1.47-9.34), if they are obese. Infants from these pregnancies are significantly more likely to require neonatal resuscitation in the form of free flow oxygen (OR 1.57, 95% CI 1.03, 2.42) than macrosomic infants of non-obese mothers. Thus, co-existing maternal obesity and macrosomia increases the risk of adverse pregnancy outcomes.

Aim To assess current methods of prediction of adverse pregnancy outcomes, develop a prediction model and assess diet and life style in preventing preeclampsia. Methods Meta-analyses performed to assess the role of abnormal 1st trimester biomarker levels in predicting PE and the predictive accuracy of 2nd trimester UAD indices for stillbirth. A prospective observational study was performed to assess the efficacy of maternal characteristics, biomarkers, arteriography and UADs for predicting adverse pregnancy outcomes. Previously published 1st trimester PE prediction models were validated using data collected from the observational study. A systematic review on the effect of diet and life style based metabolic risk modifying interventions on PE was performed. Results The review of biomarkers found that abnormal levels were particularIy associated with early onset PE. The stillbirth review demonstrated a three-four fold increased risk of still birth with abnormal UAD. 1045 women were included for analysis in the prospective observational study. Our models' detection rate (false positive rate of 15%) was 72% for PE; 48% PIH; 30 % SGA < 10th centile; 57% SGA < 5th centile and 67% stillbirth. In the validation study the observed discrimination ability in the derivation studies ranged from 0.70 to 0.954. When validated against the study cohort, the AUC varied importantly, ranging from 0.504 to 0.833. Dietary interventions were shown to reduce the risk of PE by 33%, with no reduction in risk with mixed interventions or fatty acid supplementation. Conclusion The high heterogeneity of studies in the systematic reviews makes it difficult to draw firm conclusions regarding the use of biomarkers or UADs in screening for pregnancy complications. Our prospective study showed a role for haemodynamics as part of routine 1st trimester screening for assessing the risk of hypertensive disease in pregnancy.

Reproductive health patterns in post-Soviet Central Asian countries Abstract This study aims to evaluate reproductive health patterns among post-Soviet Central Asian republics since their independence. The reproductive health indicators of individual countries were researched and compared. Furthermore, cluster country groups among selected post-Soviet, post-Socialist and capitalist countries were identified based on certain reproductive health indicators for the beginning and the end of the research period. The subsequent research was focused on 1999 Kazakhstan Demographic and Health Survey data. This thesis explores statistically significant factors influencing pregnancy outcomes in the country. According to the results, never married, urban women, women of Ukrainian, Russian, and other ethnicities, women living in the East and North regions were more likely to terminate a first pregnancy by an induced abortion rather than giving a live birth. Additionally, the same categories were proven to be statistically significant using the Poisson regression analysis, except the regions were shown to be the West and the North. Keywords: post-Soviet Central Asia, reproductive health, maternal mortality, pregnancy outcomes

Warfarin is the most widely prescribed oral anticoagulant used for the long-term treatment and prevention of thromboembolic events. Its administration is challenging as it may result in bleeding-related deaths, inadequate anticoagulation and fetal teratogenesis, including fetal warfarin syndrome. A number of environmental and genetic factors contribute to interindividual warfarin dosage variability. The CYP2C9 and VKORC1 genes explain 40- 50% of this variability. The aim of this study was to determine the frequency of known and any new variants in these genes in the SA black population, and correlate these variants and a small subset of environmental factors to dosage variability and pregnancy outcomes. I sequenced the exons and intron/exon boundaries of the CYP2C9 and VKORC1 genes in 100 random black control and 113 patient samples that had at least one pregnancy on warfarin. I observed six previously described CYP2C9 variants, 27 novel CYP2C9 variants, and three previously described VKORC1 variants. 14 of these variants were observed at an allele frequency of 0.02. Of these 14, six appear to decrease (all of which are CYP2C9 variants) and four increase (2 CYP2C9 variants and two VKORC1 variants) warfarin dosage requirement. These 14 CYP2C9 and VKORC1 variants along with a small subset of environmental factors account for 45.3% of warfarin dosage variability in the SA population. I observed an increase in the number of poor pregnancy outcomes in patients on high doses of warfarin. These results allow us to predict the maintenance dose of warfarin in SA black patients better, thereby reducing the risk of adverse effects, and identify those at risk of having a poor pregnancy outcome.

Faculty of Health Sciences School of Patholgy 8601804k erine.gregersen@nhls.ac.za / The oral anticoagulant, warfarin, when administered in pregnancy, can cause warfarin embryopathy, fetal central nervous system abnormalities, spontaneous abortion and fetal intrauterine death. Women with prosthetic heart valves usually require warfarin in pregnancy because of their high risk for thromboembolic complications. Anticoagulation regimens in pregnancy in these women aim to balance the fetal effects of warfarin with maternal risks of thromboembolism. This study was conducted by structured interview of 124 black urban South African women of childbearing age, who had at least one warfarin-exposed pregnancy. The study aimed to determine the pregnancy outcomes in this cohort, their awareness of the effects of warfarin in pregnancy, and what management practices, as reported by them, had occurred with regard to their anticoagulation in pregnancy and what genetic counselling they had received. There was a significant difference in outcome between warfarin-exposed and non-exposed pregnancies; 55.2% (123/223) of warfarin-exposed pregnancies ended in the birth of an abnormal baby, spontaneous abortion or intrauterine death. The warfarin embryopathy rate was estimated at 4.5 – 5.4%. Most women reported having been given information about warfarin in pregnancy, though their awareness about the personal and fetal effects of warfarin was often inaccurate. Of warfarin-exposed pregnancies, 95% were reportedly exposed during critical weeks six to ten of pregnancy, and >50% after 36 weeks. Only 5/124 (4%) interviewees had genetic counselling. Poor pregnancy outcomes, lack of awareness about the effects of warfarin in pregnancy, and management practices at odds with international regimens are all areas highlighted by this study that require urgent attention in this high-risk group of women.

Gestational diabetes (GDM) is a potentially serious disorder requiring timely diagnosis and management to prevent adverse maternal and fetal outcomes. Of increasing concern today, when treating the woman with GDM, is the need to provide every woman with an intensive management plan to optimise the likelihood of favourable pregnancy outcomes. Early identification of those women with GDM who require insulin therapy in addition to diet therapy would be beneficial in the planning and standardisation of clinical management protocols, to enhance pregnancy outcomes and increase cost benefits with improved allocation of resources. The aim of this study was to evaluate the ability of the fasting plasma glucose level (FPG) at diagnosis to predict an increased risk to the fetus and the need for insulin therapy in a pregnancy complicated by GDM. A prospective longitudinal study design and recruitment by convenience sample was used. Data were obtained from 327 women and their babies. Diagnosis of GDM was made by a 75 gram oral glucose tolerance test (OGTT) using Australasian Diabetes in Pregnancy Society (ADIPS) criteria with the exception of seven women diagnosed on a blood glucose level >11.1mmol/l. Following consent of the women data were collected by a self report questionnaire and the medical record system at three points; at first intervention, following delivery and at the postpartum OGTT. Demographic, social, medical, maternal and neonatal outcome data were collected. The management protocol was similar for all of the women. Following nutritional intervention any woman who could not meet the glycemic targets of <= 5mmol/l fasting and/or <= 6.5mmol/l two hours postprandial was commenced on insulin therapy. The women had a mean age of 32 years, body mass index (BMI) of 25.7 and parity of 2 (range 1-12). Diagnosis was made at an average of 30 weeks and 70 women required insulin therapy with a mean dose of 34 IU per day, commencing at a mean of 31 weeks gestation. Mean birthweight was 3400G. Of the babies 12% were >4000G. Congenital abnormalities occurred in 3%, neonatal morbidities in 2% and there was 1 death in utero. Logistic regression analysis found the following significant associations: Increasing maternal BMI was related to increasing FPG levels at diagnosis and the requirement of higher insulin doses. There was a negative linear relationship to weight gain. Ethnicity was associated with maternal BMI and ethnicity with BMI was associated with birthweight in the specific ethnic group. BMI with insulin therapy as a covariate and the FPG value at OGTT were predictive of persistent glucose intolerance in 14% of women postpartum. Each value of the OGTT was a significant predictor of the need for insulin therapy as a function of the week of gestation. The FPG level was the statistical model of best fit. A 50% probability for requiring insulin was reached with a FPG at diagnosis of 4.0 mmol/l if tested at 10 weeks gestation, 5.1mmol/l at 20 weeks and 6.1 mmol/l at 30 weeks (p<.001). These results support the substantive research aim of the study. The model has the power to predict the probability (risk) of requiring insulin therapy based on the maternal FPG level at the OGTT according to the week of gestation. The study results demonstrate that glucose intolerance is linked to a number of adverse maternal and fetal outcomes in a continuous and graded fashion. The degree of reversibility of maternal and fetal risk through therapeutic interventions such as nutrition therapy, blood glucose monitoring, exercise and active patient participation aimed at improving glucose tolerance is unknown. Therefore, the rationale for, and feasibility of, new treatment strategies such as the application of this statistical model as a management approach require large scale randomised intervention studies, oriented toward measuring maternal and fetal outcomes amongst different populations.

Philosophiae Doctor - PhD / The aim of the study was to detect the prevalence of AV and its associated bacteria with preterm delivery in the Western Cape, South Africa. Furthermore, it sought particularly to examine and investigate the predictive value of GBS and E. faecalis for preterm delivery (PTD). It also aimed to establish other factors which may predict adverse pregnancy outcomes. Three hundred and one pregnant women were recruited from four different antenatal in the Western Cape, South Africa. The study conformed with the Declaration of Helsinki (2013). Maternal data was collected from a questionnaire and maternal medical records. Vaginal and rectal swabs were collected and microscopically examined for AV, followed by culture characterization of GBS and E. faecalis. Antimicrobial susceptibility testing was also performed. In this study, AV was detected in 79 (26.2%) of the 301 pregnant women, and GBS and E. faecalis isolated from 50 (16.6%) and 21 (7.0%) respectively. GBS serotype V was the predominant serotype, followed by serotype III. Pulse field gel electrophoresis (PFGE) profile analysis for both GBS and E. faecalis yielded a total of 24 restrictions profiles for GBS and 16 for E. faecalis. Multivariable analysis revealed that parity, gravidity, vaginal discharge, urinary tract infection, and smoking were significantly associated with PTD. The results from the study provides improved guidelines maternal screening of pregnant women. The early detection of AV-related bacteria may significantly reduce maternal and neonatal morbidity.