Screening for preeclampsia

Background: Preeclampsia (PE) affects 2-3% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality. It is thought to occur due to abnormal placentation characterised by poor trophoblastic invasion resulting in oxidative stress and release of factors that promote endothelial dysfunction and inflammation. The current approach of screening for PE is to identify risk factors from maternal demographic characteristics and medical history. In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) has issued guidelines recommending that women should be considered to be at high risk of developing PE if they have any 1 high-risk factor or any 2 moderate-risk factors. With this approach, defined by NICE, at a screen positive rate of 11%, the detection rate (DR) for total PE is 35%. Such a screening approach has two main limitations. Firstly, it does not provide individualised, patient specific results and secondly, it does not allow the integration of biomarkers for improving the performance of the screening test. However, the integration of such biomarkers is essential in achieving an effective screening strategy for PE. Objectives: The aims of the papers included in this thesis are firstly, to identify and quantify the effects of variables from maternal characteristics and medical history on specific biochemical markers, secondly to present a model for standardising biochemical marker measurements in all three trimesters of pregnancy into multiples of the normal median (MoM) values, thirdly to summarize the distribution of MoM values in pregnancies with normal outcomes and those that subsequently develop PE and fourthly, to examine the potential improvement in performance of screening for PE at 30-34 weeks’ gestation by maternal factors alone with the addition of biophysical and biochemical markers. Methods: The data for this thesis were derived from prospective screening of women with singleton pregnancies attending for three routine hospital visits at 12, 22 and 32 or 36 weeks’ gestation. We have recorded a series of maternal characteristics and history, measured the maternal weight and height as well as the uterine artery pulsatility index (UTPI), mean arterial pressure (MAP), serum concentration of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLIT-1). The pregnancy outcomes were obtained from the hospital maternity records or the general medical practitioners of the women. Bayes theorem was used to combine the a priori risk from maternal factors with various combinations of biomarker MoM values. The potential value of biophysical and biochemical markers in improving the performance in screening for PE were evaluated. Results: Firstly, in pregnancies that developed PE, serum PlGF is decreased, while sFLIT-1, MAP and UTPI were increased, secondly, the separation in MoM values from normal is greater with earlier than later gestational age at which delivery for PE is necessary and thirdly, the slope of the regression lines of PlGF MoM with gestational age at delivery in pregnancies that develop PE increases with gestational age at screening. Combined screening at 30-34 weeks’ gestation by maternal factors, MAP, UTPI, PlGF, and sFLIT-1 predicted 98% (95% confidence interval, 88- 100%) of preterm PE and 49% (95% confidence interval, 42-57%) of term PE, at a false positive rate of 5%. Conclusions: This thesis has demonstrated that biophysical and biochemical markers increase significantly the performance of screening for PE and as a result the timing and content of clinical visits can be defined by the patient-specific risk of developing the disease. The vast majority of women would be screened low risk and these can follow the routine antenatal care, whereas those few who are high risk could be directed to a more specialized pathway, where early therapeutic interventions prophylactically may lead to the prevention of the disease and close follow-up will reduce the adverse consequences of PE