Establishing a Differential Marker Profile for Pregnancy Complications Near Delivery

Abstract

Objective: The aim of this work was to define a differential marker profile for pregnancy complications near delivery. Methods: We enrolled pregnant women who were referred to the outpatient pregnancy clinic of the University Medical Center, Ljubljana, Slovenia, due to symptoms of pregnancy complications and women with a history of pregnancy complications attending the high-risk hospital clinic for close surveillance. They were evaluated for prior risk and were tested for biophysical and biochemical markers at the time of enrolment. Biochemical markers included the pro- and anti-angiogenic markers, along with additional previously reported markers of potential value, all tested by various formats of immuno-diagnostics. Biophysical markers included blood pressure, sonographic markers, and EndoPAT. Statistical differences were determined with Kruskal-Wallis and Mann-Whitney tests for continuous parameters, and Pearson χ² for categorical values. p < 0.05 was considered significant. Results: The cohort included 125 pregnant patients, 31 developed preeclampsia (PE) alone (13 were <34 weeks’ gestation), 16 had intrauterine growth restriction (IUGR) alone (12 were <34 weeks), 42 had both IUGR and PE (22 were <34 weeks), and 15 had an iatrogenic preterm delivery (PTD; 6 were <34 weeks). Twenty-one were unaffected and delivered a healthy baby at term. Mean arterial blood pressure and proteinuria were significantly higher in PE and PE+IUGR but not in pure IUGR or PTD. In PE, IUGR, and PE+IUGR, the levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) were significantly higher, while placental growth factor (PlGF) was very low compared to unaffected controls and PTD. PE, IUGR, and PE+IUGR also had a high anti-angiogenic ratio (sFlt-1/PlGF) and a low proangiogenic ratio of PlGF/(sFlt-1+Eng). Levels of inhibin A were significantly higher in pure PE across subgroups but had many extreme values, which made it a poor differentiator. Higher uterine artery Doppler pulsatility indexes were detected in PE, IUGR, and PE+IUGR, with similar resistance indexes and peaks of systolic velocity. A significantly different marker level between PE and IUGR was found using arterial stiffness that was 10 times higher in PE; concurrently with an increase of the reactive hyperemia index, both were accompanied by a slight increase in placental protein 13. Higher tumor necrosis factor alpha (TNFα) differentially identified iatrogenic very early PTD (<34 weeks). Conclusion: Arterial stiffness can serve as a major marker to differentiate PE (with/without IUGR) from pure IUGR near delivery. TNFα can differentiate iatrogenic early PTD from other complications of pregnancy and term IUGR.