<b><i>Objective:</i></b> The aim of this work was to define a differential marker profile for pregnancy complications near delivery. <b><i>Methods:</i></b> 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. <i>p</i> &#x3c; 0.05 was considered significant. <b><i>Results:</i></b> The cohort included 125 pregnant patients, 31 developed preeclampsia (PE) alone (13 were &#x3c;34 weeks’ gestation), 16 had intrauterine growth restriction (IUGR) alone (12 were &#x3c;34 weeks), 42 had both IUGR and PE (22 were &#x3c;34 weeks), and 15 had an iatrogenic preterm delivery (PTD; 6 were &#x3c;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 (&#x3c;34 weeks). <b><i>Conclusion:</i></b> 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.

Background Identifying the risk factors for preeclampsia (PE) is essential for the implementation of preventive actions. In the present study, we aimed at exploring the association between total gestational weight gain (GWG) and PE. Methods We performed a population-based cohort survey of 98,820 women with singleton pregnancies who delivered in Slovenia from 2013 to 2017. Aggregated data were obtained from the National Perinatal Information System (NPIS). The main outcome measure was the incidence of PE. The main exposure variable was total GWG standardized for the gestational duration by calculating the z-scores. The associations between total GWG and PE stratified by pre-pregnancy body mass index (BMI) categories adjusted for a variety of covariates were determined using multivariable logistic regression. We calculated the crude odds ratio (OR) and adjusted odds ratio (aOR) with a 95% confidence interval using a two-way test. Results Excessive GWG was associated with increased odds of PE in all pre-pregnancy BMI categories. The increase in the odds of PE by 445% was the highest in underweight women and by 122% was the lowest in obese women. Low GWG was associated with decreased odds of PE in all pre-pregnancy BMI categories except in normal-weight women with a GWG below −2 standard deviation (SD) and underweight women. The decrease in the odds of PE by 67% was the highest in obese women and by 41% was the lowest in normal-weight women. Conclusion Excessive GWG is a significant risk factor for PE, especially in underweight women, while low GWG is an important protective factor against PE, especially in obese women.

Aim To evaluate effectiveness and safety of therapeutic plasma exchange (TPE) and dextran‐sulfate plasma adsorption (DSA) for extracorporeal removal of soluble Fms‐like tyrosine kinase‐1 (sFlt‐1) as part of expectant management of preeclampsia at extremely preterm gestational age. Methods Retrospective case series of six patients with preeclampsia at <28 weeks of gestation, treated with DSA or TPE. Laboratory results, clinical characteristics and neonatal outcomes were collected from charts and National Perinatal Information System. Results Fetal growth restriction (FGR) was diagnosed in all cases. Pregnancy was prolonged for a median of 14 (range 5‐74) days from admission and 10 (3‐73) days from first apheresis. A mixed effects model showed a decrease in sFlt‐1 and sFlt‐1/PlGF ratio during DSA/TPE (significant effect of time [before/after]), which was comparable between DSA and TPE (no effect of procedure type). Median absolute reduction in sFlt‐1 was 42% (inter‐quartile range [IQR] 13%‐57%) during DSA and 34% (16%‐40%) during TPE; for sFlt‐1/PlGF ratio it was 29% (22%‐36%) and 38% (29%‐42%), respectively. All procedures were well tolerated by fetuses. Anaphylactoid reaction, often with angioedema, occurred in 4/6 patients undergoing DSA and was attributed to bradykinin activation. One patient developed wound hematoma after cesarean section, possibly attributed to depletion coagulopathy. Conclusions As potential novel treatment of early preeclampsia, a non‐selective and widely available TPE was comparable to DSA regarding sFlt‐1 reduction but was associated with fewer side‐effects. Both seem to allow maternal stabilization and pregnancy prolongation even when early preeclampsia is complicated by FGR.

Objective—the objective of this study was to assess the accuracy of placental growth factor (PlGF), soluble Fms-like Tyrosine Kinase 1 (sFlt-1), and endoglin (sEng) in the diagnosis of suspected preeclampsia (PE) with and without fetal growth restriction (FGR) near delivery. Methods—this is a secondary analysis of a dataset of 125 pregnant women presenting at the high risk pregnancy clinic with suspected PE, FGR or PE + FGR in the University Medical Center of Slovenia. The dataset included 31 PE cases, 16 FGR cases, 42 PE + FGR cases, 15 cases who developed with unrelated complications before 37 weeks (wks) (PTD), and 21 unaffected controls who delivered a healthy baby at term. We also analyzed a sub-group of women who delivered early (<34 wks) including 10 PE, 12 FGR, 28 PE + FGR, and six PTD. Clinical management adhered to hospital guidelines. Marker levels were extracted from the dataset and were used to develop Receiver Operating Characteristic (ROC) curves and to calculate the area under the curve (AUC), the detection rates (DRs), and the false positive rates (FPRs). Previously published marker cutoffs for yes/no admission to hospital wards were extracted from the literature. Negative and positive predictive values (NPVs and PPVs) were evaluated for their value in determining whether hospital admission was required. Non-parametric tests were applied for statistical analysis; p < 0.05 was considered significant. Results—near delivery, all the pro-and anti-angiogenic markers provided diagnostic (ROC = 1.00) accuracy for the early (<34 wks) group of FGR. Diagnostic or near diagnostic (ROC = 0.95) accuracy was achieved by all marker for early PE + FGR but lower accuracy was achieved for early PE. For all cases, all markers, especially PlGF reached diagnostic or near diagnostic accuracy for FGR and PE + FGR. At this accuracy level, they can contribute to the clinical management of FGR, and PE + FGR. All the markers were less accurate for all PE cases. The use of published cutoffs was adequate for clinical management of FGR, whether early or for all cases, using an NPV > 90%. For PE + FGR, the PPV value approached 100%, especially for early cases, and can thus be implemented in clinical management. Neither NPV nor PPV were high enough for managing all cases of PE. There was no added value in measuring the PlGF/(sFlt-1 + sEng) ratio. Conclusion—This is the first study on a Slovenian population. It shows that near-delivery angiogenic biomarkers tests may be useful for confirming the diseases in cases where there is a diagnostic doubt. However, the clinical use of the biomarkers needs to be weighed against resources available and degree of certainty of the diagnosis made with and without them for managing suspected FGR and PE + FGR requiring delivery <34 wks, where they are very accurate, and furthermore in the management of all cases of FGR and FGR+PE. The markers were less accurate for the clinical diagnosis of PE.

Objectives—To conduct a secondary analysis of prediction accuracy of biophysical markers for suspected Preeclampsia (PE), Fetal Growth Restriction (FGR) and the two combined near delivery in a Slovenian cohort. Methods—This was a secondary analysis of a database of a total 125 Slovenian pregnant women attending a high-risk pregnancy clinic due to suspected PE (n = 31), FGR (n = 16) and PE + FGR (n = 42) from 28–39 weeks gestation and their corresponding term (n = 21) and preterm (PTD, n = 15) controls. Data for Mean Arterial blood Pressure (MAP) and Uterine artery pulsatility index (UtA PI) estimated by Doppler sonography were extracted from the database of patients who were tested at admission to the high-risk clinic with the suspected complications. The reactive hyperemia index (RHI), and the Augmentation Index (AIX%) were extracted from the patient database using measured values obtained with the assistance of the Endo PAT, a device set to measure the signal of the peripheral arterial tone (PAT) from the blood vessels endothelium. Linear regression coefficients, Box and Whisker plots, Area under the Curve (AUC) of receiver Operation Characteristic (ROC) curves, and multiple regression were used to assess the marker accuracy using detection rate (DR) and false-positive rate (FPR) and previously reported cut-offs for estimating the positive and negative predictive value (NPV and PPV). The SPSS non-parametric statistics (Kruskal Wallis and Mann–Whitney) and Spearman’s regression coefficient were used to assess marker accuracy; p < 0.05 was considered significant. Results—MAP values reached diagnostic accuracy (AUC = 1.00, DR = 100%) for early PE cases delivered < 34, whereas UtA Doppler PI values yielded such results for early FGR < 34 weeks and the two combined reached such accuracy for PE + FGR. To reach diagnostic accuracy for all cases of the complications, the Endo PAT markers with values for MAP and UtA Doppler PI were required for cases near delivery. Multiple regression analyses showed added value for advanced maternal age and gestational week in risk assessment for all cases of PE, FGR, and PE + FGR. Spearman’s regression coefficient yielded r > 0.6 for UtA Doppler PI over GA for PE and FGR, whereas for RHI over BMI, the regression coefficient was r > 0.5 (p < 0.001 for each). Very high correlations were also found between UtA Doppler PI and sFlt-1/PlGF or PlGF (r = −0.495, p < 0.001), especially in cases of FGR. Conclusion—The classical biophysical markers MAP and UtA Doppler PI provided diagnostic accuracy for PE and FGR < 34 wks gestation. A multiple biophysical marker analysis was required to reach diagnostic accuracy for all cases of these complications. The UtA Doppler PI and maternal serum sFlt-1/PlGF or PlGF were equally accurate for early cases to enable the choice of the markers for the clinical use according to the more accessible method.