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In fact, not many reports are available on the normal progress of, and fluctuations in, plasma cholesterol levels, and a degree of inflammation and oxidative stress markers during pregnancy, not to mention the consequences for the offspring. Plasma cholesterol levels during pregnancy increase between 25-50% and the majority of pregnant women develop gestational hypercholesterolemia.51,52 Changes in maternal cholesterol metabolism are generally considered to be a natural phenomenon not directly posing a risk for cardiovascular disease in both mother and progeny. Cholesterol is an essential component for adequate development of the fetus, as it is an integral part of cell membranes. It is, however, not known at which threshold the effects of gestational hypercholesterolemia switch from being beneficial to the embryo/fetus to detrimental. This not only accounts for hypercholesterolemia, but also for hypocholesterolemia during pregnancy, which is associated with preterm delivery and reduced birth weight.53-55

Since we demonstrated in this thesis that maternal hypercholesterolemia most probably is not the most important trigger for intrauterine programming of athero-susceptibility and manifestation of pathology, (Chapter 3,4) the role of apoE, inflammation and oxidative stress on intrauterine programming should be investigated. In a recent study, a weak association between elevated maternal C- reactive protein, an indicator of inflammation and oxidative stress, and atherosclerosis development in the offspring was found.56 Examination of other markers of systemic inflammation, such as TNFα_{, IL-6, IL-7, IL-8, serum amyloid A,}

fibrinogen, and markers of endothelial cell function like sCAMs, may shed more light on the role of inflammation and oxidative stress on intrauterine programming.57-59 Altogether, we would like to recommend the initiation of an epidemiological prospective follow-up study in which, besides routine assessment of plasma cholesterol levels, a search for, and identification of, inflammatory and oxidative stress markers will be performed. This will increase our understanding on metabolic changes during pregnancy and the balance between maternal production and fetal needs. In addition, general monitoring may identify a high-risk population of women for which prevention and treatment strategies can be developed that benefit both mother and child.

In gestational hypercholesterolemia, the most conventional treatment strategy is dietary intervention.60 In spite of moderate cholesterol-lowering effects, the CARDIPP study showed that dietary intervention has limited effects on biomarkers for inflammation.61 Dietary intervention therefore appears not to be the most ideal method to reduce the maternal burden. Many lipid-lowering and anti- inflammatory drugs exist that are prescribed in case of hypercholesterolemia or other metabolic disorders. However, they can not be safely prescribed during pregnancy.62 Statins, the most potent drugs that can be prescribed for cholesterol- lowering are contraindicated during pregnancy. This is the result of limited and inconclusive experimental data. Studies on the incidence of congenital birth defects after use of statins in the first trimester of pregnancy revealed a limited numbers of abnormalities among live births.63-65 There is still debate about whether or not these abnormalities are the consequence of statin exposure. The involvement of statins in spontaneous abortions in early pregnancy has never been examined. Furthermore, resultant cholesterol lowering and other pleiotropic effects66,67 most probably exert more subtle effects than induction of congenital birth defects. These influences have not been identified thus far. Finally, we have to realize that cholesterol lowering may establish cholesterol levels below the threshold necessary to provide for the fetal needs thereby harming the unborn. The results of this thesis could be of interest for the pharmaceutical industry as we provide new perspectives on how intrauterine atherosclerotic risk factors possibly exert their effects (Chapter 6,7).

General Discussion

137 inconsistent results in animals2,75-78 and clinical trials in human demonstrated no beneficial effects.79-81 Beta-carotene supplementation even significantly increased cardiovascular disease risk in humans.82-84 Overall, antioxidant treatment strategies are not as effective as expected and use in pregnant women therefore should not be recommended.

In addition to all the effort that has been put in studies on statins and antioxidants, progress has been made in the development of treatment regimes that act via anti-inflammatory effects. A growing body of evidence suggests a role for inflammatory pathways in adverse reproductive outcomes.85 The two main intervention strategies are immunosuppressive drugs and immunization by vaccines. As far as anti-inflammatory drugs are concerned, it is not known whether use has harmful effects on the mother and fetus. Future studies have to be performed to gain more insight. The development of many vaccines is still in the pre-clinical phase, but they seem very promising (reviewed by Riley and colleagues

86

). In the setting of intrauterine programming of adult cardiovascular disease, Yamashita and colleagues performed maternal immunization studies with oxLDL and KLH before pregnancy.87 Atherosclerosis in the offspring was significantly reduced in case of maternal immunization with oxLDL. Whether vaccines in the future can be prescribed to pregnant women, without adverse effects on the mother and fetus, remains to be established.