A top priority in pre-eclampsia research: development of a reliable and inexpensive urinary screening test
Authors: Marco Scioscia, Gustaaf A Dekker, Gérard Chaouat, Lalita Dawonauth, Ralf Dechend, Debra Goldman-Wohl, Erry Gumilar, S Ananth Karumanchi, Douglas B Kell, Thomas W Rademacher, Sarah Robertson, Shigeru Saito, Sicco Scherjon, Anne C Staff, Manu Vatish, Pierre-Yves Robillard
Journal: The Lancet Global Health (2019)

Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity worldwide, with an estimated 60 000 pre-eclampsia-related maternal deaths per year.1Khan KS Wojdyla D Say L Gülmezoglu AM Van Look PF WHO analysis of causes of maternal death: a systematic review.Lancet. 2006; 367: 1066-1074Summary Full Text Full Text PDF PubMed Scopus (2404) Google Scholar This complication of human pregnancy has increased in incidence in the past decade and can be avoided by timely and effective care (secondary prevention).2Campbell OM Graham WJ Strategies for reducing maternal mortality: getting on with what works.Lancet. 2006; 368: 1284-1299Summary Full Text Full Text PDF PubMed Scopus (1129) Google Scholar Pre-eclampsia is defined by new hypertension and organ damage (mainly involving the kidney and sometimes the liver) that can evolve into eclamptic seizures, maternal stroke, and abruptio placentae. Despite extensive research by obstetricians, paediatricians, immunologists, cardiologists, epidemiologists, and anthropologists, pre-eclampsia remains a complex and heterogenous disorder of elusive pathophysiology. We formed the International Group of Reproductive Immunology, Immunological Tolerance and Immunology of Preeclampsia in 1998, aiming to study the causes and address key gaps in the knowledge of pre-eclampsia. Our consensus is that the condition arises because of altered placental development as demonstrated by impaired secretion of pro-angiogenic placental growth factor (PlGF), which leads to placental release into the maternal circulation of angiogenic factors, including soluble endoglin (sEng) and soluble fms-like tyrosine kinase (sFlt). These factors are strongly correlated with development of maternal syndrome (hypertension, proteinuria, and organ damage) and are shown to increase at or before onset of clinical symptoms.3Levine RJ Maynard SE Qian C et al.Circulating angiogenic factors and the risk of preeclampsia.N Engl J Med. 2004; 350: 672-683Crossref PubMed Scopus (2622) Google Scholar, 4Duhig KE Myers J Seed PT et al.Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial.Lancet. 2019; 393: 1807-1818Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar In The Lancet, Emmanuel Bujold and colleagues5Bujold E Chaillet N Kingdom J Placental growth factor testing for suspected pre-eclampsia.Lancet. 2019; 393: 1775-1776Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar commented on a controlled trial from the PARROT group describing testing of pro-angiogenic placental growth factor to optimise pre-eclampsia diagnosis.4Duhig KE Myers J Seed PT et al.Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial.Lancet. 2019; 393: 1807-1818Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar Bujold and colleagues5Bujold E Chaillet N Kingdom J Placental growth factor testing for suspected pre-eclampsia.Lancet. 2019; 393: 1775-1776Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar highlighted that this test was used in large, high-resource maternity units; however, the investigators suggested to evaluate the additional role of ultrasound in future research to improve clinical outcomes. Since the highest incidence of pre-eclampsia occurs in low-income and middle-income countries that rely on basic means,1Khan KS Wojdyla D Say L Gülmezoglu AM Van Look PF WHO analysis of causes of maternal death: a systematic review.Lancet. 2006; 367: 1066-1074Summary Full Text Full Text PDF PubMed Scopus (2404) Google Scholar it would be most appropriate to focus on developing an inexpensive, easy-to-administer (with minimal discomfort), reliable, and validated test. On the basis of research progress to date, several research priorities were agreed during a workshop on Reunion Island, France, in December 2018, which involved 22 participants recruited from research groups worldwide. The first and paramount priority is to achieve a reliable and inexpensive screening test, which represents the main issue to be addressed: optimising clinical assistance to prevent maternal and fetal morbidity. Urinary tests remain the best inexpensive option that could be administered in low-resource settings and even rural areas in low-income countries. Therefore, patients might be identified and referred to specific clinical pathways offering increased surveillance to avoid medical interventions being ineffective because of late presentation. Various candidate biomarkers and approaches exist, but the most exciting and tractable options as urinary tests are detection of urinary misfolded proteins using azo-dye Congo Red,6Rood KM Buhimschi CS Dible T et al.Congo red dot paper test for antenatal triage and rapid identification of preeclampsia.EClinicalMedicine. 2019; 8: 47-56Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar adipsin,7Wang T Zhou R Gao L et al.Elevation of urinary adipsin in preeclampsia: correlation with urine protein concentration and the potential use for a rapid diagnostic test.Hypertension. 2014; 64: 846-851Crossref PubMed Scopus (24) Google Scholar and inositol phosphoglycans P-type.8Williams PJ Gumaa K Scioscia M Redman CW Rademacher TW Inositol phosphoglycan p-type in preeclampsia: a novel marker?.Hypertension. 2007; 49: 84-89Crossref PubMed Scopus (36) Google Scholar Kara Rood and colleagues6Rood KM Buhimschi CS Dible T et al.Congo red dot paper test for antenatal triage and rapid identification of preeclampsia.EClinicalMedicine. 2019; 8: 47-56Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar did a prospective study in a university setting in Ohio, USA, using a semi-quantitative analysis based on a specifically developed paper-based urine test kit. Urinary adipsin is another valid candidate that showed high sensitivity (90%) and good specificity (78%) in a longitudinal study in a university hospital in China.7Wang T Zhou R Gao L et al.Elevation of urinary adipsin in preeclampsia: correlation with urine protein concentration and the potential use for a rapid diagnostic test.Hypertension. 2014; 64: 846-851Crossref PubMed Scopus (24) Google Scholar Like the PARROT study,4Duhig KE Myers J Seed PT et al.Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial.Lancet. 2019; 393: 1807-1818Summary Full Text Full Text PDF PubMed Scopus (101) Google Scholar these two studies focused on the potential of the test to optimise diagnosis, whereas screening potential was minimally investigated. A longitudinal study in a low-income country9L'Omelette AD Dawonauth L Rademacher L et al.New insights into early and late onset subgroups of preeclampsia from longitudinal versus cross-sectional analysis of urinary inositol-phosphoglycan P-Type.J Reprod Immunol. 2018; 125: 64-71Crossref PubMed Scopus (5) Google Scholar also identified inositol phosphoglycans P-type as one of several metabolic molecules in maternal urine that show identification of women destined to develop pre-eclampsia 3–4 weeks before onset of clinical symptoms is possible. Other emerging urine biomarkers that showed positive performances are neutrophil gelatinase-associated lipocalin and complement biomarkers, such as C5a and C5b-9.10Acestor N Goett J Lee A et al.Towards biomarker-based tests that can facilitate decisions about prevention and management of preeclampsia in low-resource settings.Clin Chem Lab Med. 2016; 54: 17-27Crossref PubMed Scopus (9) Google Scholar Detection and quantification of inositol phosphoglycans P-type, neutrophil gelatinase-associated lipocalin, and complement biomarkers are achieved via ELISA; therefore, development of a simple method on the basis of urine strips or similar should be feasible. Clinical studies including urinary routine testing during every antenatal visit would test improvement of early diagnosis compared with routine antenatal care and capacity for tertiary prevention.2Campbell OM Graham WJ Strategies for reducing maternal mortality: getting on with what works.Lancet. 2006; 368: 1284-1299Summary Full Text Full Text PDF PubMed Scopus (1129) Google Scholar Given the availability of several candidate urinary biomarkers, we propose that diagnostic companies should allocate resources towards development of a low-cost urine test that is specific for pre-eclampsia diagnosis, as this test would have substantial benefits, particularly in low-income and middle-income countries where resources for expensive blood tests might not be available. TWR reports being a co-author on inositol phosphoglycans pre-eclampsia publications while on the University College London Medical School board. TWR was a coinventor on an InositolPhospho Glycan pre-eclampsia diagnostic patent, which has now lapsed. TWR provides laboratory reagents to academic groups for pre-eclampsia clinical trials. SAK reports consultancy work for Roche and Thermofisher and receiving a research grant from Siemens during the writing of this Comment; being a founder and advisory board member of Aggamin Pharmaceuticals outside the submitted work; Preeclampsia Biomarker patents with royalties paid to Beth Israel Deaconess Medical Center; and being a member of the Scientific Advisory Board for the Pre-eclampsia Foundation. All other authors declare no competing interests.