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Approximately 27% of Kenya’s 50 million people live in urban areas. The majority (56%) live in slums or slum-like settings, with limited access to functional [public] health care in a setting where poverty and insecurity are rampant. In 2015/16, one in every three Kenyan lived below the international poverty line (US$1.90 per day in 2011 per person). The poor, who are disproportionately affected by cardiovascular diseases (CVD), lack livelihood opportunities due to unemployment and are likely to possess low levels of education or be ignorant about CVD risk factors. The goal of this study was to determine the link between socioeconomic factors and risk and mortality from CVD, with the aim of informing interventions for prevention and control of CVD in underserved populations in Kenya. Based on data from the 2015 STEPWise survey on non-communicable diseases risk factors (STEPs), we determined that three in four Kenyan adults possessed between four and six non-communicable diseases (NCD) risk factors from among insufficient physical activity, smoking/tobacco use, harmful alcohol consumption, overweight and obesity, hypertension, and diabetes, indicating an emerging NCD epidemic in the country. Age, sex, level of education and socioeconomic status were key determinants. In slums of Nairobi, the understanding of and perceptions towards NCD and CVD were influenced by literacy levels, while ignorance towards risk factors, stigma and poverty, and perceived high cost of health care negatively affected care-seeking and treatment-adherence for CVD. Mortality from CVD was inversely correlated with gainful unemployment and higher levels of education. Investing in educating the public on CVD and risk factors, while empowering their access to livelihood opportunities are socioeconomic interventions that can enhance primordial prevention and treatment-adherence for CVD in Kenya.

To attain the Sustainable Development Goal of ending preventable new-born deaths and reducing neonatal deaths to at least 12 per 1000 births, urgent attention is required in low- and middle-income countries which contribute the most to the global burden of neonatal deaths. Mobile health (mHealth) can potentially improve neonatal health outcomes. We designed and implemented an mHealth intervention that provided easy access to neonatal health guidelines for clinical decision-making for health workers in the Eastern Region of Ghana. We evaluated the impact of the intervention on institutional neonatal mortality and investigated the ‘how and why’ of the observed intervention effect. Sixteen districts in the Eastern Region were randomized into a 2-arm cluster-randomized controlled trial (8 intervention and 8 control clusters per arm) that assessed the impact of the intervention on neonatal mortality over an 18-month period. To understand the possible explanatory mechanism for the observed intervention effect, three sub-studies were undertaken. Firstly, we assessed utilization of the intervention and measured the correlation between the requests made and the incidence of deliveries and neonatal morbidities in the intervention clusters. Secondly, we assessed health worker adherence to neonatal protocols before and during the trial period using in-patient clinical records. Thirdly, to understand how and why the intervention was utilized as observed, we performed a single case study with each cluster as an embedded sub-unit of analysis using key informant interviews and focus group discussions with the intervention users, and manually analysed the data for themes. This thesis showed that health workers readily used the intervention to access neonatal health guidelines. The use of the intervention however, declined over time due to individual health worker, organizational, and technological factors as well as client perception of health worker intervention usage. During the trial period, there was a raise in neonatal deaths in both arms study arms. The odds of neonatal death was 2.09 (95% CI (1∙00;4∙38); p=0∙051) times higher in the intervention arm compared to the control arm (adjusted odds ratio). The correlation between the number of protocol requests and the number of deliveries per intervention cluster was 0∙71 (p=0∙05). The higher odds of neonatal death in the intervention arm is possibly due to unmeasured and unadjusted confounding due to limitations in the data structure of the national health database of Ghana, unintended use of the intervention and problems with births and deaths registration at the study sites. Many other neonatal health improvement programmes (unrelated to our mHealth intervention) were observed in the control arm compared to the intervention arm during the trial period. Adherence to neonatal health protocols improved in both study arms and this may be related to these other neonatal improvement programmes that took place particularly in the control arm clusters. Technological factors alone are unlikely to influence outcomes. This thesis highlights the importance of validating successful programmes and interventions in settings where they are to be implemented. Harmonized rather than fragmented efforts are needed to scale up mHealth interventions that have been proven to be effective in a given context.

HIV is a public health concern with currently 37 million people living with HIV (PLHIV) globally. Around 70% of PLHIV reside in sub-Saharan Africa (SSA). Antiretroviral therapy (ART) has turned HIV from a deadly disease into a chronic condition. HIV has been associated with a 2-fold increased risk of cardiovascular disease (CVD) in high-income countries. The aim of this thesis is to get insight into the role of HIV and ART on CVD risk in SSA, while considering the role of immune activation. In two systematic reviews no clear association between any marker of immune activation and CVD risk could be detected. Second, the frequency of CVD risk factors like hypertension and obesity was compared between PLHIV and HIV-negative people and PLHIV turned out to have fewer CVD risk factors then HIV-negatives. Third, the occurrence of subclinical CVD was assessed with surrogate markers. In one study, including almost 2000 participants at a rural site, PLHIV who are on ART had more subclinical CVD from the age of 30 years compared to HIV-negative people. This result could not be confirmed in another study including 550 participants as no association between HIV, ART and subclinical CVD was found. However, this study included less participants over the age of 50 years, and there was more viral suppression than in the rural study population. In conclusion, HIV is associated with less CVD risk factors but, despite this, with an increase in subclinical CVD in PLHIV on ART from the age of 30 years.

Universities aim for deep learning. Two trends may threaten the achievement of deep learning, namely the massification of students and the increasing choice for online education by universities. Considering these trends, this dissertation examines the extent to which instructors can promote deep learning in online higher education. As a consequence of the often asynchronous and typed interaction, instructors experience specific challenges in online education. Scalable instructor interventions are described that can be used to meet these challenges. Additionally, mechanisms have been identified that are triggered and lead to deep learning. The intervention 'peer feedback' is zoomed in on. This intervention leads to deep learning because students question the feedback of peers more than that of an instructor, and therefore think longer about it. Providing peer feedback is shown to be just as valuable as receiving it. Results can be used by instructors in designing and teaching. Universities are advised to review their teaching strategy on the basis of current trends and the results of this dissertation.

Urbanization and migration have been increasing in the last few decades and have been associated with rising levels of cardiovascular diseases (CVD) and its risk factors in urban populations in low-and middle-income countries and migrant populations in high income countries. Transitioning of societies and resulting changes in lifestyle is a major driving force but key specific factors are not known. The aim of this thesis was to assess CVD risk among sub-Saharan African populations by assessing (i) the knowledge of and perception of CVD risk (ii) the differences in the burden of CVD risk and associated risk factors and (iii) explore CVD risk prediction and determinants of CVD mortality in sub-Saharan Africa (SSA). First, despite the high burden of CVD among sub-Saharan African populations, knowledge of CVD risk was very low. In a systematic review, less than half of study participants from included studies had good knowledge of CVDs and/or risk factors. Low knowledge of CVDs, risk factors and clinical symptoms is strongly associated with the low levels of educational attainment and rural residency. Second, we found that CVD risk vary according to geographical contexts. Compared to rural Ghana, CVD risk was significantly increased for Ghanaian men living in Europe. Additionally, this risk increased with duration of stay in Europe. Third, we observed contextual differences in risk factors of CVD and their resultant association with CVD risk. We found an inverse association between a ‘mixed’ and ‘rice, pasta, meat and fish’ DP and CVD risk among Ghanaian populations in urban Ghana whereas a ‘roots, tubers and plantain’ DP was directly associated with increased 10-year risk CVD risk in rural Ghana. Psychosocial stress was also associated with CVD risk among Ghanaian populations. Recent negative life events were associated with a high estimated CVD risk in non-migrants while higher levels of perceived discrimination were associated with a high estimated CVD risk in migrants. Sitting height, a marker of early life exposure was also associated with CVD risk. Currently, screening tools for the management of CVD are less available in SSA. However, we observed that current CVD risk algorithms, developed on different populations might not appropriate estimate CVD risk for the SSA population. We found that CVD prediction with the same algorithm differs for the migrant and home populations. Finally, based on a 10-year follow data on South African population, age, smoking, hypertension and HIV status were found to be major determinants of CVD mortality. This suggests that together with previously established risk factors for CVD, HIV infection could be a potentially important risk factor for CVD risk prediction in this population. In conclusion, this thesis recommended the implementation of effective policy measures and increased commitment to improving public awareness and effective surveillance mechanisms in SSA. However, the socio-cultural context should be taken into consideration and used to address knowledge gaps. Preventive measures for CVD among migrants should take into consideration ethnic differences, as well as address the challenges in access to healthcare among minority populations.

Hypertensive disorders of pregnancy are important causes of maternal morbidity and mortality. This thesis describes the nature of hypertensive disorders of pregnancy in Ghana, a low-and-middle-income country (LMIC), and provides evidence on the use of prediction models for early identification of pregnant women at risk of the hypertensive disorders of pregnancy. We estimated the incidence of pregnancy induced hypertension (PIH)across districts in the highly urbanized Greater Accra region and the predominantly rural Upper West region of Ghana, using routine hospital data. The quality of the health management information system (HMIS) data was also assessed. Key variables for routine assessment of PIH such as blood pressure at antenatal visits, weight and height were observed to be 95% to 100% complete. The incidence of PIH differed significantly between the Greater Accra region and Upper West regions. Prevalence of obesity among pregnant women in Greater Accra region was significantly higher than that of women in Upper West region. We recommend an improvement in the quality of routine data to track maternal health indicators. A systematic review of prediction models for gestational hypertension and preeclampsia was conducted with the aim of assessing the methodological quality of the prediction modeling studies and to find prediction models that can be applied in LMIC. Seventy percent of the prediction models reviewed combined biomarkers with maternal clinical characteristics. Of the thirty-two prediction models reviewed, only three had been developed in a LMIC. The use of biomarkers, though enhancing performance of prediction models, may limit the applicability of prediction models in most LMIC because these biomarkers are currently not routinely measured in these settings. Research to develop affordable, easy-to-use uterine artery Doppler imaging equipment and diagnostic assays for serum biomarkers is recommended so the prediction models can be used in low and middle income countries to improve maternal health. We developed and validated a prediction model for gestational hypertension using maternal clinical characteristics obtained at the antenatal clinic visit. The c-statistic was 0.70 and 0.68 for the development and validation cohorts respectively. We also assessed whether adding the biomarkers Pregnancy Associated Plasma Protein-A (PAPP-A) and Placental Growth Factor (PlGF) to maternal clinical characteristics improved the prediction of a previously developed model for gestational hypertension in a cohort of Ghanaian pregnant women.The Area Under the Receiver Operating Characteristic Curve (AUC) was used to assess the predictive ability of the models. The area under the curve (AUC) of the model with only maternal clinical characteristics was 0.75 and 0.89 for multiparous and primigravid women respectively and this increased to 0.82 and 0.95 respectively after inclusion of PAPP-A and PlGF. We concluded that adding the biomarkers to maternal characteristics in a prediction model for gestational hypertension improved predictive ability. Finally we discussed the application of the findings of these studies to improving maternal health in LMIC. Research and development of low cost assays for biomarkers should be prioritized to enable the use of prediction models to identify women at risk of hypertensive disorders of pregnancy early and institute appropriate measures for care.

Background: Cardiovascular disease (CVD) remains the leading cause of death worldwide. The top priority of secondary prevention is to control modifiable risk factors. However, current cardiovascular risk factor management remains inadequate and monitoring programs, like clinical audits, are lacking. Objectives: i> to summarize the importance of clinical audits in daily practice; ii> to describe CVD risk factor recording and management in routine practice; iii> to assess potential determinants within and between different geographic regions; and iv> to summarize the use of cardiovascular medication in China. Results: The consistency and representativeness of existing clinical audits were still limited. SURF CHD (SUrvey of Risk Factors Coronary Heart Disease) was a straightforward and targeted clinical audit to simplify the recording and monitoring of routine CVD risk factors. SURF recruited 10,186 CHD patients in 11 countries among three different regions (Europe, Asia, and the Middle East). Recording and management of CVD risk factor was generally poor. Over 80% of participants had inadequate risk factor management with less than five risk factors being controlled. SURF found several characteristics had significant impacts on cardiovascular risk factor management. Women were less likely to achieve targets for total cholesterol (odds ratio 0.50, 95% confidence interval 0.43-0.59), low-density lipoprotein cholesterol (LDL) (OR 0.57, 95% CI 0.51-0.64), and glucose (OR 0.78, 95% CI 0.70-0.87), or to be physically active (OR 0.74, 95% CI 0.68-0.81) or non-obese (OR 0.82, 95% CI 0.74-0.90). Furthermore, to control three or more risk factor was less likely to be reached by women (OR 0.84. 95% CI 0.74-0.95), and those aged

Breast cancer is the most frequently diagnosed cancer in women worldwide. There were over three million five-year breast cancer survivors worldwide in 2012. Cardiovascular disease (CVD) is an important cause of death in breast cancer survivors. Breast cancer therapies such as radiation therapy, certain types of chemotherapy, and targeted treatment increase the risk of CVD, especially in patients with pre-existing CVD risk factors including higher age, hypertension, diabetes mellitus, and a history of CVD. Coronary artery calcification (CAC) and thoracic aortic calcification (TAC) are (subclinical) markers of atherosclerosis and are associated with a higher risk of coronary heart disease. CAC and TAC are measured on computed tomography (CT) scans. Breast cancer patients treated with radiation therapy routinely undergo a CT scan of the breasts for radiotherapy planning, on which the coronary arteries and aorta are visible. Calcifications in these areas can be quantified without exposing patients to additional radiation and without additional costs. Currently, presence of CAC and TAC is not routinely assessed in breast cancer patients on RT planning CT scans. However, systematic incorporation of CAC and TAC scores in breast cancer treatment decision potentially reduces cardiovascular mortality and morbidity. In this thesis, the first steps towards a more systematic approach of cardiovascular risk assessment in breast cancer patients are taken. We first estimated the risk and determinants of CVD in breast cancer patients. Secondly, we investigated the prevalence of CAC and TAC on radiotherapy planning CT scans in Western (i.e. the Netherlands) and Asian (i.e. Singapore) breast cancer patients. For this, we used a new developed software, based on the state-of-the-art deep learning technique, that automatically measures CAC and TAC on radiotherapy planning CT scans. In the Netherlands, the absolute ten-year risk of death from CVD after breast cancer decreased from 56 per 1,000 women in 1996 to 41 in 2005 (relative decrease of 23.9%). The relative risk of death from CVD is 77% higher in Dutch breast cancer patients compared to Dutch women without breast cancer, when pre-existing CVD risk factors are taken into account. Prevalence of coronary artery calcification (CAC) and thoracic aorta calcification (TAC) is considerable and increases with age. CAC occurred in up to one third of patients aged under 70 years. Comparing patients from the Netherlands with patients from Singapore, CAC was more prevalent in patients aged over 70 years from Singapore (70%) than in patients aged over 70 years from the Netherlands (55%). TAC was prevalent in two third of patients from the Netherlands and Singapore. The performance of automatic CAC and TAC scoring was good compared to manual scoring in planning CT scans from the Netherlands and Singapore. The new developed automatic software is a promising fast technique (less than one minute per scan) to systematically detect calcifications on planning CT scans of patients treated with radiotherapy. In the future, calcification status may be used to screen patients for CVD risk, and to indicate who could benefit from cardiac monitoring, cancer therapy with reduced risk of cardiotoxicity and/or cardioprotective medication.

Clinical trials serve a key role in drug development by providing scientific knowledge on the risks and benefits of medical treatments or therapies. Conducting a clinical trial is a time-consuming endeavor which typically requires a large financial budget. It is therefore important to critically reflect on how resources are being spent. Indeed, the efficiency of clinical trial conduct is becoming an increasingly active topic of research and discussion, in view of rising healthcare costs. Estimates suggests that a considerable portion (15 to 30 percent) of a phase III clinical trial budget is spent on the monitoring of the local investigators (i.e. the treating physicians) and their teams. Traditionally, this is the responsibility of a Clinical Research Associate (CRA), who is employed by the sponsor or contract research organization. The CRA visits the local centers on regular intervals and spends a large portion of his/her time comparing all submitted data against the source data, correcting any discrepancy that is detected. This thesis examines and further develops alternative monitoring and trial management strategies which are aimed to conduct clinical trials more efficiently, while at the same time preserving or even improving data quality. Mainly, it focuses on methods that reduce the reliance on the physical presence of the CRA on the local centers and make better use of centrally available data, and it reflects on specific aspects of trial management for which the effectiveness has been the subject of discussion. After a general introduction, the thesis first focuses on the use of statistical sampling methodology to reduce the effort of source data verification. Next, it examines how central statistical monitoring can be used for the detection of data fabrication (i.e. possible fraud). Third, to improve selection and management of clinical trial sites, it is evaluated to which extent center-level information can predict their performance in terms of meeting recruitment targets. Furthermore, the impact of outcome misclassification is assessed, and the value of so-called adjudication to overcome this problem is critically evaluated. As a last topic, the thesis addresses application of so-called ‘risk-based monitoring’ procedures in the context of pragmatic trials. The thesis ends with a general discussion and framework on the topic of clinical trial monitoring.

Randomized controlled clinical trials (RCTs) are considered fundamental to the optimization of health care decision-making. Today, the drug development and evaluation process is dominated by so-called explanatory RCTs. Such RCTs are carried out in highly-controlled conditions to deliver the best evidence supporting market authorization of new pharmaceutical interventions. However, patients in explanatory phase III trials are very different from the actual patients who visit health care facilities in the context of “real world” clinical care. In the real world patients tend to be older, sicker and less keen on taking their medication. And what they care about is not necessarily bone density and systolic blood pressure, but rather whether the new drug keeps them out of the hospital. The focus on ‘ideal’ patients and situations means that for many patients it is uncertain whether a new drug on the market works better in real life than any of the other alternatives available. The misalignment between efficacy data (can the drug work?) and effectiveness data (does the drug work in real life) suggests that explanatory RCTs cannot do all the work. The collection of so-called “real world data” has been proposed to complement the evidence-base for making health care decisions. Pragmatic randomized trials are considered one of the strategies to obtain real world evidence. They contrast explanatory RCTs by question and design, since they aim to answer questions about the effectiveness of health interventions in routine care conditions. Recent calls have even gone out to design such trials already at the time of regulatory market approval of new interventions. Exploring ways to implement pragmatic trials in the process of drug development is a laudable goal in itself. Nevertheless, departing from the classic paradigm of explanatory RCTs, especially as early as prior to market authorization, raises the question of ethical acceptability. In order to sustain public support for clinical research, this thesis therefore examines the ethical issues related to pragmatic trials. Specifically, the question is addressed whether modifications to the regulatory informed consent process would be ethically defensible. This thesis concludes with three ways to promote pragmatism in randomized trials in an ethically responsible manner. Firstly, a few relatively accessible methods are discussed to increase the practical relevance of randomized phase III trials and early post-marketing research. Secondly, adjusting the timing of the trial could provide a solution for obtaining timely real world answers in cases where a conflict arises between a pragmatic design feature and an ethical requirement. In cases for which these methods are insufficient, some pragmatic trials could potentially be conducted in the early post-market phase with less stringent requirements. Such trials would have to address questions of evident social value, under the condition that the risks are minimal, the research is infeasible otherwise and there is a sufficient degree of transparency and freedom of choice for patients.

Approximately 300.000 women die annually during pregnancy, childbirth or within 42 days after the delivery. Most of these deaths occur in women living in low- and middle-income countries (LMIC) in sub-Saharan African and South-East Asia, and could have been prevented with access to quality maternal health care. The objective of this thesis is to explore strategies to improve maternal and perinatal outcomes in an urban sub-Saharan African middle-income country context. Most of the studies in this thesis were conducted in Accra in Ghana. This will be approached through the identification of the impact of specific risk factors on adverse pregnancy outcomes, specifically obesity, hypertensive disorders of pregnancy and HIV/AIDS. The second part of this thesis focuses on hypertensive disorders of pregnancy, which occur more frequently in urban settings, and explores the role of biomarkers for prediction in hypertensive disorders of pregnancy. The third part explores approaches to improve the quality of care, including the assessment of the quality of care in hospitals, the effect of maternal insurance on maternal health services utilization, task shifting of care in hospital settings, and an innovative strategy to prevent hypertensive disorders of pregnancy.

Early life nutrition is one of the most substantial environmental factors that shapes future health. This extends from the women’s nutritional status prior to conception and during pregnancy to the offspring’s nutritional conditions during infancy and early childhood. During this critical period, various body organs are undergone growth and development at incredible rates and programming of body systems take place. This thesis basically provides evidence on the associations between nutritional circumstances early in life, particularly during preconception and gestation period, with newborn health outcomes. We outlined this thesis into three parts. The first part (chapters 2, 3, 4, and 5) mainly focuses on in utero Ramadan exposure as nutritional determinants that may influence newborn health outcome. The second part (chapters 6 and 7) provides evidence about the effect of maternal nutrition status early in pregnancy on the development of pregnancy complications and newborn outcome. In the third part of this thesis (chapter 8), we described a protocol of a randomized trial on breastfeeding which is aimed to investigate the effect of breastfeeding on health outcomes during the first years of life. Part 1 begins with a description of various factors that predict women’s adherence to Ramadan fasting during pregnancy (Chapter 2). Although the health effects of Ramadan fasting during pregnancy are still unclear, it is important to identify various factors behind women’s adherence to Ramadan fasting. The results of our cross sectional study among Indonesian women showed that demographic factors such as age, income, education, or employment do not influence fasting adherence, but higher pre-pregnancy body mass index (BMI), earlier gestational age, opposition from husband and fear of adverse fasting effects on their own or the baby’s health do. These factors need to be addressed properly during counseling. In Chapter 3, we present the association between Ramadan exposure and fasting during pregnancy with newborn’s birth weight and the risk of gestational hypertension. In our Indonesian cohort of pregnant women, we found that birth weight was generally higher with Ramadan exposure as compared to without exposure. Analyses among women with Ramadan exposure revealed that although women who fasted had significantly lower nutrient intake in Ramadan, no different in the newborn’s birth weight nor in the risk of gestational hypertension was found. These findings suggest that a transient life style modification that occurs with Ramadan does not seem to affect pregnancy outcomes investigated. In Chapter 4, we show that among women of Moroccan and Turkish background living in The Netherlands, Ramadan fasting during the first trimester of pregnancy was associated with lower birth weight. No difference of birth weight was found if the fasting took place later in pregnancy. This suggests that the effect of Ramadan fasting on newborn’s birth weight may depend on the timing exposure. Furthermore, differences in finding as compared to the study in Indonesian women indicate that the effects may (partially) be influenced by culture or dietary habits as well as the length of fasting duration. Chapter 5 addresses the association between in-utero Ramadan exposure with various birth outcomes. We analyzed 1,987,124 newborns from 11 birth cohorts of the Perinatal Registry of the Netherlands (Perined), 139,322 of these were classified as Muslims. No clinically relevant effect of Ramadan exposure was found, including on birth weight, Apgar score, congenital anomalies, sex ratio, gestational duration and perinatal mortality. In Part 2, we focus on the effects of maternal nutrition status early in pregnancy on pregnancy outcomes. We present the associations between hyperemesis gravidarum, as a model of nutritional disturbance, on the development of placental dysfunction disorders in Chapter 6. Using the data from our prospective cohort study in Jakarta, Indonesia, we found that women who experienced severe hyperemesis had significantly lower birth weight newborns. Hyperemesis did not affect the development of placental dysfunction disorders (gestational hypertension, preeclampsia, stillbirth, and miscarriage), other newborn health measures (SGA, low birth weight, Apgar score, and gestation length), nor the placental dimension (placental weight and placental-weight-to-birth-weight ratio). In Chapter 7, we elaborate the effect of women’s prepregnancy body mass index (BMI) on their blood pressure during pregnancy. Using the data from our prospective cohort study in Jakarta, Indonesia, we showed that pre-pregnancy BMI determined women’s systolic and diastolic blood pressure level during pregnancy. Higher prepregnancy BMI was also associated with higher risk of gestational hypertension and preeclampsia. These associations imply that pre-pregnancy (cardiovascular) risk factors strongly influence women’s blood pressure. This finding also suggests the importance of prevention of pregnancy complications which should be done prior to pregnancy. Part 3 (Chapter 8), we described a study protocol of a randomized trial on breastfeeding optimization (BRAVO) that is on going in Jakarta, Indonesia. This study is aimed to provide evidence about the short and long term health effects of breastfeeding, mainly on the children’s cardiovascular and metabolic risks. Pregnant women with low intention to breastfeed are randomly allocated into either usual care or receiving an add-on breastfeeding optimization program which includes antenatal, perinatal, postnatal intervention, and special support for working mothers. Primary outcomes include breastfeeding rate, lung function, and blood pressure during the first year of life and vascular/cardiac characteristics which will be measured when the children are between 4 to 5 years old. So far, BRAVO has been successfully conducted with satisfactory completeness of follow up. Finally in Chapter 9 (general discussion), we discuss our findings in light of implementable intervention measures, both in the context of maternal and child health and in the prevention of later health consequences. Findings from the etiologic studies described in this thesis about maternal nutrition, including Ramadan (fasting) exposure in pregnancy, hyperemesis gravidarum, pre-pregnancy BMI, and breastfeeding, although may not directly translatable to practice, could provide indications for prevention and directions future research in this area.

Overwhelming data from clinical trials show that pharmacological interventions with aspirin, statins and blood pressure (BP)-lowering agents considerably reduce the risk of cardiovascular events and total mortality. Therefore, current international treatment guidelines recommend to prescribe statins, BP-lowering agents, and, where benefits outweigh risks, antiplatelet therapy with little constraints to individuals at high risk of cardiovascular disease, such as patients with established cardiovascular disease or those at equivalent high risk. However, in clinical practice large gaps between indicated therapy and prescribed medication can be observed worldwide, with very low rates of use of effective therapies in middle- and low-income countries. Various barriers may underlie suboptimal prescribing rates and low treatment continuation rates in high-risk patients, which include the complexity of preventive treatment regimens for both doctors and patients, inequities in health care delivery and medication costs. A fixed-dose combination pill, frequently called a cardiovascular polypill, containing aspirin, a statin and ≥1 BP-lowering agents has been suggested to moderate prescription to indicated therapy and reduce physicians’ and patients’ barriers in order to optimize the prevention of cardiovascular diseases in the general population, in subjects with elevated vascular risk and in high-risk patients. The aim of this thesis is to provide evidence on the efficacy, safety and tolerability of the polypill in patients at high risk of cardiovascular disease. In addition, attention is given to aspects of feasibility, such as timing of intake and patients’ preferences regarding therapy. Patients with established cardiovascular disease or those at equivalent high risk were shown to often already use a combination of aspirin, a statin and BP-lowering agents as recommended in usual care. A combination of these drugs was shown to be effective in preventing (subsequent) cardiovascular events. Therefore, patients at high risk of cardiovascular could be considered as the ‘low hanging fruit’ for the implementation of a polypill-based treatment strategy. Switching to a polypill containing aspirin, simvastatin and two BP lowering agents was found to result in improved adherence and lower levels of low-density lipoprotein (LDL)-cholesterol and systolic BP among patients at high risk of cardiovascular disease. Additionally, the risk of cardiovascular disease was approximately 10% lower compared to continuing usual care irrespective of the treatment received at baseline. Differences in atherosclerosis as measured with carotid intima media thickness or 24-hour ambulator BP between the polypill group and the usual care group could not be shown. Importantly, carotid intima media thickness progression and ambulatory BP were not adversely effected by the polypill-based treatment strategy. The polypill was well tolerated. As the components of the polypill are used at different times of the day, the optimal time for using the polypill was uncertain. It was shown that the reduction of LDL-cholesterol and systolic BP was optimal when the polypill was administered in the evening compared to the morning. Importantly patients highly preferred to be treated with a polypill over the individual pills, resulting in higher adherence levels. The results of this thesis strongly suggest a potential role for the polypill in the prevention of cardiovascular disease.