Early prediction of preeclampsia
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Preeclampsia (PE) is a major cause of perinatal and maternal morbidity and mortality. In the United Kingdom, the National Institute for Clinical Excellence (NICE) has issued guidelines on routine antenatal care recommending that at the booking visit a woman’s level of risk for PE should be determined and the subsequent intensity of antenatal care should be based on this risk assessment. This method relies on a risk scoring system derived from maternal characteristics and medical history; the performance of screening by this method is poor with detection of less than 50% of cases of preterm-PE and term-PE. The objective of this thesis is to develop a method for the estimation of the patient-specific risk for PE by combining the a priori risk based on maternal characteristics and medical history with the results of biophysical and biochemical markers obtained at 11-13 weeks’ gestation. Such early identification of high-risk pregnancies could lead to the use of pharmacological interventions, such as low-dose aspirin, which could prevent the development of the disease. The data for the thesis were derived from two types of studies: First, prospective screening in 65,771 singleton pregnancies, which provided data for maternal factors and serum pregnancy associated plasma protein-A (PAPP-A). In an unselected sequential process we also measured uterine artery pulsatility index (PI) in 45,885 of these pregnancies, mean arterial pressure (MAP) in 35,215 cases and placental growth factor (PLGF) in 14,252 cases. Second, cases-control studies for evaluating the ten most promising biochemical markers identified from search of the literature; for these studies we used stored serum or plasma samples obtained during screening and measured PLGF, Activin-A, Inhibin-A, placental protein-13 (PP13), P-selectin, Pentraxin-3 (PTX-3), soluble Endoglin (sEng), Plasminogen activator inhibitor-2 (PAI-2), Angiopoietin-2 (Ang-2) and soluble fms-like tyrosine kinase-1 (s-Flt-1). A competing risk model was developed which is based on Bayes theorem and combines the prior risk from maternal factors with the distribution of biomarkers to derive patient-specific risk for PE at different stages in pregnancy. The prior risk was derived by multiple regression analysis of maternal factors in the screening study. The distribution of biophysical and biochemical markers was derived from both the screening study and the case-control studies. The prior risk increased with advancing maternal age, increasing weight, was higher in women of Afro-Caribbean and South-Asian racial origin, those with a previous pregnancy with PE, conception by in vitro fertilization and medical history of chronic hypertension, type 1 diabetes mellitus and systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS). The estimated detection rate (DR) of PE requiring delivery at <34, <37 weeks’ gestation and all PE, at false positive rate (FPR) of 10%, in screening by maternal factors were 51, 43 and 40%, respectively. The addition of biochemical markers to maternal factors, including maternal serum PLGF and PAPPA, improved the performance of screening with respective DRs of 74, 56 and 41%. Similarly, addition of biophysical markers to maternal factors, including uterine artery PI and MAP, improved the performance of screening with respective DRs of 90, 72 and 57%. The combination of maternal factors with all the above biophysical and biochemical markers improved the respective DRs to 96, 77 and 54%. The findings of these studies demonstrate that a combination of maternal factors, biophysical and biochemical markers can effectively identify women at high-risk of developing PE.