First trimester screening for maternal and fetal disease: A search for novel biomarkers

Preeclampsia is a serious disorder that occurs only during pregnancy. It is rapidly progressive condition characterized by high blood-pressure and proteinuria. Preeclampsia affects 2% of pregnant women and is a leading cause of maternal and perinatal morbidity and mortality worldwide. Yearly preeclampsia contributes to 50.000-76.000 maternal and 500.000 infant deaths and approximately $7billion in total costs. In the Netherlands, annually about 2.000 women develop preeclampsia and 10 of them die due to it. Additionally, preeclampsia is associated with substantial risks of perinatal morbidity and mortality due to concomitant intrauterine growth restriction, iatrogenic prematurity and stillbirth.It is also associated with substantial health problems later in life for both mother and child. In the Netherlands the incidence of maternal mortality due to preeclampsia is greater than in other European countries. Analysis of all preeclampsia related maternal deaths (2000-2004) revealed that in 96% of the cases, delay of the diagnosis and substandard-care were the major cause. The clinical practice strongly suggests that, in case of surviving patients, the timing of recognition, referral to a specialized center and start of treatment is correlated to the severity of the complications. Recent meta-analysis of Bujold (2009) suggests that prevention of preeclampsia with low-dose aspirin, if started before 16 weeks of gestation, is highly effective in a high-risk group and reduces up to 50% of preeclampsia cases. It is therefore of major importance, to identify patients at high-risk already at the beginning of the pregnancy through an adequate screening test, thereby detecting the disease ahead of its clinical onset, enabling suitable pregnancy care, and ensuring better pregnancy outcomes for both mother and child. Currently, in the Netherlands there is no routine screening program for preeclampsia. The general purpose of this PhD thesis was the development of an effective first-trimester prenatal screening test for preeclampsia. For this purpose, set of (novel)biomarkers is needed that is capable to detect the presence of pathologic conditions already early in pregnancy. This PhD-project aimed four out of five phases of biomarker development for early detection of preeclampsia: Phase-1: was based on exploration of pathophysiology of preeclampsia and search for potential biomarkers through systematic literature study, data-mining and high-throughput metabolomics technique Phase-2: focused on the development and evaluation of a screening test containing biomarkers derived from phase-1 and able to non-invasively distinguish between healthy and at-risk individuals Phase-3: validated the test in well described retrospective cohorts Phase-4: applied the test in a prospective cohort to evaluate the predictive value and assess practical feasibility of the screening program. Phase-5: cost-effectiveness analysis of the screening and treatment belongs to the future prospectives. The general conclusion of this thesis is: The knowledge of preeclampsia pathogenesis led to the discovery of several first-trimester biomarkers and the development of different mathematical models that combine these markers in order to predict preeclampsia.The findings of this thesis confirm that the combination of measurements of uterine artery Doppler, maternal characteristics, mean arterial pressure and multiple serum biomarkers appears promising in early prediction of preeclampsia