Abstract
Objective
This study aimed to evaluate the clinical and prognostic value of various inflammatory and metabolic indices in identifying of early-onset (EO-PE) and late-onset preeclampsia (LO-PE) and in predicting composite adverse maternal outcomes (CAMO), composite adverse perinatal outcomes (CANO), and disease severity.
Methods
This retrospective cohort study included 625 singleton pregnant women followed at a tertiary center between January 1, 2023, and January 1, 2025. The study group comprised 320 preeclamptic women (170 EO-PE < 34 weeks, 150 LO-PE ≥ 34 weeks), while 305 gestational age-matched healthy pregnancies served as controls (155 early controls, 150 late controls). Preeclampsia cases were further classified into 155 severe and 165 mild cases. The indices analyzed included uric acid/albumin ratio (UA/Alb), fibrinogen/uric acid ratio (Fib/UA), uric acid/creatinine ratio (UA/Cr), creatinine/body weight ratio (Cr/BW), AST/platelet ratio (AST/PLT), AST/ALT ratio, and fibrosis indices (FIB-4 and FIB-5). Composite adverse maternal outcomes (CAMO) include the presence of at least one of the following maternal outcomes: thrombocytopenia, renal dysfunction, hepatic dysfunction, HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), disseminated intravascular coagulation (DIC), pulmonary edema, eclampsia, and admission to the maternal intensive care unit (ICU). Composite adverse neonatal outcomes (CANO) include the presence of at least one of the following adverse outcomes: transient tachypnea of the newborn, respiratory distress syndrome, need for continuous positive airway pressure, need for mechanical ventilation, need for phototherapy, neonatal hypoglycemia, intraventricular hemorrhage, necrotizing enterocolitis, neonatal sepsis, 5th minute APGAR score < 7, neonatal intensive care unit (NICU) admission, placental abruption, and preterm birth.
Results
The UA/Alb ratio and Fib/UA ratio were the most strongly associated with EO-PE and LO-PE, with high discriminative accuracy (AUC = 0.831 and 0.888, respectively). These indices also showed strong associations with CAMO, CANO, and disease severity. In contrast, the AST/ALT ratio was not significantly associated with PE discrimination, severity, CAMO, or CANO. The AST/PLT ratio and FIB-4 were significantly associated with both EO-PE and LO-PE, while FIB-5 was only associated with EO-PE. Both FIB-4 and FIB-5 were significantly linked to CAMO and CANO in EO-PE cases, but not in LO-PE. Both indices were also associated with severe preeclampsia. Although the Cr/BW ratio was associated with disease severity, it showed limited value in distinguishing EO-PE or LO-PE from the control group and was only related to CAMO and CANO in EO-PE.
Conclusion
Our study identified UA/Alb and Fib/UA ratios as the most informative indices for classifying EO-PE and LO-PE, assessing CAMO and CANO risk, and evaluating disease severity. The high AUC values support their potential clinical applicability. Conversely, the AST/ALT ratio was not significantly associated with preeclampsia diagnosis, disease severity, differentiation of CAMO or CANO.
Keywords: Preeclampsia, Uric acid/albumin ratio, Fibrinogen/uric acid ratio, Creatinine/body weight ratio, AST/PLT ratio, AST/ALT ratio, FIB 4, FIB 5
Introduction
Preeclampsia is a systemic pregnancy complication characterized by hypertension, proteinuria, and/or organ dysfunction after 20 weeks of gestation [1]. It affects 2–8% of pregnancies globally and is a leading cause of maternal-fetal morbidity and mortality [2]. Although the pathophysiology of preeclampsia has not been fully elucidated, the condition is strongly associated with endothelial dysfunction, inflammation, oxidative stress, and vascular abnormalities, largely driven by placental ischemia, inadequate trophoblast invasion, and overexpression of antiangiogenic factors such as sFlt-1 and sEng [3]. Systemic vascular dysfunction in preeclampsia triggers microangiopathic processes, leading to fibrin deposition and intravascular coagulation, which, in turn, cause widespread endothelial injury [4]. This vascular damage affects multiple organ systems, contributing to hepatic, renal, and cardiovascular dysfunction [4–6]. Hepatic involvement is characterized by sinusoidal obstruction and ischemia, while renal impairment leads to reduced glomerular filtration, proteinuria, hyperuricemia, and impaired creatinine metabolism [7, 8]. These disruptions further exacerbate systemic circulatory disturbances, compromising placental perfusion, increasing fetal hypoxia, and elevating the risk of adverse pregnancy outcomes.
In recent years, the clinical application of various biochemical indices for evaluating systemic dysfunction in preeclampsia has gained increasing attention. These indices, derived from routine laboratory parameters, provide a non-invasive method for assessing disease severity and predicting adverse maternal and fetal outcomes. The fibrosis-4 (FIB-4) and fibrosis-5 (FIB-5) indices, initially developed for the non-invasive assessment of hepatic fibrosis and cirrhosis, have been shown to correlate not only with liver function but also with systemic inflammation, vascular dysfunction, and organ damage [9–11]. Similarly, high uric acid and creatinine levels are indicative of renal dysfunction and reduced glomerular filtration rate, potentially reflecting impaired tissue perfusion and systemic inflammation [12]. Low albumin levels are associated with increased vascular permeability, edema, and organ dysfunction [13]. Additionally, fibrin deposition in the hepatic sinusoids and renal microvasculature contributes to hepatic and renal dysfunction, further exacerbating the pathophysiological burden of preeclampsia [8]. Other indices, such as the uric acid/albumin ratio (UA/Alb) and fibrinogen/uric acid ratio (Fib/UA), serve as biomarkers of oxidative stress, endothelial dysfunction, and coagulation abnormalities, which are central to preeclampsia pathophysiology. The uric acid/creatinine ratio (UA/Cr), and the creatinine/body weight ratio (Cr/BW) reflect renal impairment, while the aspartate aminotransferase/platelet ratio (AST/PLT or APRI) and AST/alanine aminotransferase (AST/ALT) ratio provide insight into hepatic microangiopathy and platelet consumption.
This study aims to evaluate the clinical utility and prognostic value of biochemical indices that serve as indicators of systemic vascular dysfunction and organ damage in preeclampsia, with a particular focus on their ability to predict disease severity and adverse maternal-fetal outcomes. By identifying reliable and clinically applicable biomarkers, this research seeks to enhance early detection, refine risk stratification, and optimize clinical decision-making, ultimately improving maternal and neonatal outcomes in preeclampsia management.
Materials and methods
This retrospective cohort study included 625 singleton pregnant women who were followed up in the Department of Perinatology at Ankara Etlik City Hospital between January 1, 2023, and January 1, 2025. Among them, 320 patients were diagnosed with preeclampsia, including 170 with early-onset preeclampsia (EO-PE, < 34 weeks) and 150 with late-onset preeclampsia (LO-PE, ≥ 34 weeks). The control group consisted of 305 healthy pregnant women, matched for gestational age from patients seen on the same day, with 155 classified as early controls (< 34 weeks) and 150 as late controls (≥ 34 weeks). Additionally, preeclampsia cases were further classified into 155 severe and 165 mild cases [14] (Fig. 1).
Fig. 1.
Flow chart of participants
The diagnosis of preeclampsia is based on American College of Obstetricians and Gynecologists (ACOG) criteria [14]. Preeclampsia was defined as blood pressure ≥ 140/90 mmHg after 20 weeks of gestation, accompanied by proteinuria or signs of organ dysfunction. Proteinuria was identified as either a protein/creatinine ratio ≥ 0.3 in a spot urine sample or total protein ≥ 300 mg in 24-hour urine collection. Criteria for organ dysfunction included a platelet count < 100,000/mm³ (thrombocytopenia), a serum creatinine level ≥ 1.1 mg/dL or twice the baseline level (renal dysfunction), liver transaminase levels more than twice the upper reference value (hepatic dysfunction), a new-onset pulmonary edema, or neurological symptoms such as severe headache and visual disturbances. HELLP syndrome was identified by the presence of hemolysis (elevated LDH or abnormal peripheral smear), elevated liver enzymes (AST or ALT), and thrombocytopenia. Eclampsia was diagnosed in the presence of new-onset generalized tonic-clonic seizures in a woman with preeclampsia, not attributable to other causes. Disseminated intravascular coagulation (DIC) was diagnosed clinically, supported by laboratory parameters such as low fibrinogen, elevated D-dimers, prolonged coagulation times, and thrombocytopenia. EO-PE was defined as a diagnosis before 34 weeks of gestation, while LO-PE was diagnosed at or after 34 weeks. At our center, low-dose acetylsalicylic acid (ASA) prophylaxis for preeclampsia is initiated based on maternal risk assessment in accordance with ACOG guidelines [15]. Pregnant women identified as high risk are prescribed 150 mg of ASA daily before 16 weeks of gestation as a preventive measure. This standardized screening protocol is implemented across all pregnancies followed in our perinatology unit.
In addition to the preeclampsia group, a control group of healthy pregnant women without medical complications was included for comparison. Pregnant women with pre-existing medical conditions that could influence serum biomarker levels—including acute or chronic inflammatory diseases, chronic renal or liver disease, chronic hypertension, gestational or type 1–2 diabetes mellitus (DM), immunologic disorders, genetic conditions, smoking, alcohol consumption, or multiple pregnancies—were excluded. Additionally, patients taking anti-inflammatory or corticosteroid-containing medications were excluded from the study.
Patient data were extracted from medical records and the hospital information management system. Laboratory parameters were evaluated based on the first measurements taken after the diagnosis of preeclampsia and before the initiation of treatment. The inflammatory and metabolic indices assessed included uric acid/albumin ratio (UA/Alb) and fibrinogen/uric acid ratio (Fib/UA), uric acid/creatinine ratio (UA/Cr), creatinine/body weight ratio (Cr/BW), AST/PLT (APRI), AST/ALT ratio, FIB-4, and FIB-5. The formulas used for calculating FIB-4 and FIB-5 were as follows: FIB-4 = (Age (years) × AST (U/L))/(Platelet count (×10⁹/L) × (ALT (U/L))¹/²) and FIB-5 = (Albumin (g/L) × 0.3 + Platelet count (×109/L) × 0.05) − (ALP (IU/l) × 0.014 + AST/ALT ratio × 6 + 14) [16]. Composite adverse maternal outcomes (CAMO) include the presence of at least one of the following maternal outcomes: thrombocytopenia, renal dysfunction, hepatic dysfunction, HELLP syndrome, DIC, pulmonary edema, eclampsia, and admission to the maternal intensive care unit (ICU). Composite adverse neonatal outcomes (CANO) include the presence of at least one of the following adverse outcomes: transient tachypnea of the newborn, respiratory distress syndrome, need for continuous positive airway pressure, need for mechanical ventilation, need for phototherapy, neonatal hypoglycemia, intraventricular hemorrhage, necrotizing enterocolitis, neonatal sepsis, 5th minute APGAR score < 7, neonatal intensive care unit (NICU) admission, placental abruption, and preterm birth.
This study was conducted in accordance with the Declaration of Helsinki, and ethical approval was obtained from the Ankara Etlik City Hospital Ethics Committee (approval number: AESH-BADEK–2025-036). In this study, due to its retrospective nature, informed consent was waived with the approval of the Ethics Committee of Ankara Etlik City Hospital. All data were anonymized, and participant confidentiality was strictly maintained.
Statistical analysis
Statistical analysis was performed using IBM Corporation SPSS version 22.0 (IBM Corporation, Armonk, NY, USA). The Kolmogorov-Smirnov test was used to analyze conformity to normal distribution. Descriptive statistics of continuous variables are shown as mean ± standard deviation for those with normal distribution and as median (interquartile range) for those that do not. Continuous variables that were and were not normally distributed were compared using the Student’s T-test and the Mann-Whitney U test, respectively. Categorical variables are shown as n,% and were compared using Pearson’s Chi-square test or Fisher’s Exact test. Receiver Operating Characteristic (ROC) curve was applied to calculate and compare the areas under the curve (AUC) and determine the best cut-off values according to Youden index. To control for potential confounding variables, adjusted p-values were calculated using logistic regression models. For comparisons between EO-PE or LO-PE and their respective control groups, maternal age and body mass index (BMI) were included as covariates in the models. Each inflammatory or metabolic index was entered as an independent variable, and preeclampsia status (yes/no) was entered as the binary outcome. For comparisons within the preeclampsia group (e.g., CAMO vs. non-CAMO, CANO vs. non-CANO, or severe vs. mild), adjusted analyses were not performed since maternal age and BMI were not significantly different between groups in univariate comparisons. Statistical significance for all tests was defined as p-value of less than 0.05.
Based on a conventional power analysis using G-Power 3.1.9.7 software (University of Dusseldorf, Dusseldorf, Germany) assuming a medium effect size (Cohen’s d = 0.5), an alpha level of 0.05, and a desired power of 0.80, the minimum required sample size is approximately 64 participants per group, or 128 in total.
Results
A total of 625 pregnant women were evaluated in this study, including 170 women diagnosed with EO-PE, 150 women diagnosed with LO-PE, and 305 healthy pregnant women as controls. Table 1 presents the maternal characteristics, laboratory results, and umbilical artery dopplers parameters among the EO-PE, LO-PE, and control groups. Maternal age and BMI were significantly higher in both EO-PE and LO-PE groups compared to the control group (p < 0.05, for all). The use of low-dose ASA significantly more frequent in the EO-PE and LO-PE groups than in controls and was also more prevalent in EO-PE than in LO-PE (p < 0.001, for all). Although the gestational age at data collection was significantly earlier in the EO-PE group compared to the LO-PE group (p < 0.001), no significant differences were observed when comparing EO-PE vs. controls and LO-PE vs. controls (p = 0.159 and p = 0.182, respectively). Umbilical artery systolic/diastolic (S/D) ratio and pulsatility index (PI) were significantly higher in the EO-PE group compared to controls (p < 0.001, for both). The LO-PE group also had a higher UA-PI than controls (p = 0.044). Additionally, UA-S/D ratio and PI were significantly higher in EO-PE than in LO-PE (p < 0001 and p = 0.005, respectively). Hemoglobin levels were significantly higher in the EO-PE group compared to controls (p < 0.001), whereas no significant difference was observed between LO-PE and controls. The white blood cell count (WBC), neutrophil count, and lymphocyte count were significantly higher, while the monocyte count was significantly lower in the EO-PE group compared to controls (p < 0.05, for all). In the LO-PE group, WBC and neutrophil counts were significantly higher than in controls (p < 0.05, for both), whereas lymphocyte and monocyte counts did not differ significantly. Platelet counts were similar across all groups. Serum AST, ALT, lactate dehydrogenase (LDH), uric acid, and creatinine levels were significantly elevated, while albumin levels were significantly decreased in the EO-PE and LO-PE groups compared to controls (p < 0.05, for all). Fibrinogen levels were significantly higher in LO-PE than in the control group (p = 0.008), but no significant difference was observed between EO-PE and controls.
Table 1.
Comparison of maternal characteristics, laboratory results, and umbilical artery dopplers parameters of the EO-PE, LO-PE, and control groups
| EO-PE n = 170 (47.7%) |
Control n = 155 (52.3%) |
p value | LO-PE n = 150 (50%) |
Control n = 150 (50%) |
p value | EO-PE n = 170 (53.1%) |
LO-PE n = 150 (46.9%) |
p value | |
|---|---|---|---|---|---|---|---|---|---|
| Maternal age (year) | 30.8 ± 6.2 | 27.5 ± 5.4 | < 0.001a | 30.3 ± 6.6 | 28.8 ± 5.2 | 0.033a | 30.8 ± 6.2 | 30.3 ± 6.6 | 0.452a |
| Gravida | 2 (2) | 2 (2) | 0.965b | 2 (2) | 2 (2) | 0.841b | 2 (2) | 2 (2) | 0.911b |
| Parity | 1 (2) | 1 (2) | 0.382b | 1 (2) | 1 (2) | 0.958b | 1 (2) | 1 (2) | 0.439b |
| Nulliparous | 87 (51.2%) | 95 (61.3%) | 0.067c | 79 (52.7%) | 85 (56.7%) | 0.487c | 87 (51.2%) | 79 (52.7%) | 0.487c |
| In vitro fertilization | 11 (6.5%) | 0 (0%) | < 0.001d | 4 (2.7%) | 0 (0%) | 0.122d | 11 (6.5%) | 4 (2.7%) | 0.122d |
| Height (cm) | 162 (7) | 162 (10) | 0.837b | 163 (10) | 161 (8) | 0.058b | 162 (7) | 163 (10) | 0.169b |
| Weight (kg) | 85 (26) | 75 (17) | < 0.001b | 87 (24) | 77 (15) | < 0.001b | 85 (26) | 87 (24) | 0.344b |
| BMI (kg/m2) | 32.86 (11.16) | 29.14 (5.88) | < 0.001b | 33.04 (7.56) | 29.63 (6.08) | < 0.001b | 32.86 (11.16) | 33.04 (7.56) | 0.703b |
| ASA usage | 32 (19.4%) | 2 (1.3%) | < 0.001d | 18 (12.6%) | 2 (1.3%) | < 0.001d | 32 (19.4%) | 18 (12.6%) | < 0.001c |
| Gestational age at data collection (week) | 30 (4) | 31 (1) | 0.159b | 36 (2) | 36 (2) | 0.182b | 30 (4) | 36 (2) | < 0.001b |
| UA-S/D | 2.80 (0.91) | 2.52 (0.49) | < 0.001b | 2.6 (0.65) | 2.5 (0.8) | 0.164b | 2.8 (0.91) | 2.6 (0.65) | < 0.001b |
| UA-PI | 0.98 (0.28) | 0.9 (0.19) | < 0.001b | 0.9 (0.28) | 0.89 (0.29) | 0.044b | 0.98 (0.28) | 0.90 (0.28) | 0.005b |
| Hemoglobin (g/dL) | 12.1 (1.9) | 11.4 (1.7) | < 0.001b | 11.7 (1.8) | 11.9 (1.6) | 0.859b | 12.1 (1.9) | 11.7 (1.8) | 0.012b |
| White blood cell count (109/L) | 11 (3.6) | 10.77 (3.87) | 0.039b | 11.22 (3.24) | 10 (3.23) | 0.010b | 11 (3.6) | 11.22 (3.24) | 0.358b |
| Neutrophil count (109/L) | 8.15 (3.88) | 7.63 (2.95) | 0.030b | 8.25 (3.23) | 7.52 (2.72) | 0.020b | 8.15 (3.88) | 8.25 (3.23) | 0.977b |
| Lymphocyte count (109/L) | 2.9 (1.2) | 1.88 (0.52) | 0.005b | 1.89 (0.73) | 1.87 (0.76) | 0.997b | 2.9 (1.2) | 1.89 (0.73) | 0.010b |
| Monocyte count (109/L) | 0.67 (0.35) | 0.72 (0.27) | 0.040b | 0.65 (0.25) | 0.69 (0.27) | 0.431b | 0.67 (0.35) | 0.65 (0.25) | 0.957b |
| Platelet count (109/L) | 234 (97) | 236 (79) | 0.291b | 238 (97) | 239.5 (78) | 0.490b | 234 (97) | 238 (97) | 0.504b |
| AST (IU/L) | 20 (12) | 15 (6) | < 0.001b | 18.5 (11) | 15 (7) | < 0.001b | 20 (12) | 18.5 (11) | 0.447b |
| ALT (IU/L) | 13 (10) | 9 (5) | < 0.001b | 11 (6.8) | 10 (5) | 0.004b | 13 (10) | 11 (6.8) | 0.034b |
| Albumin (g/dL) | 33.65 (5.8) | 36.7 (3) | < 0.001b | 33.6 (4) | 37.15 (3.3) | < 0.001b | 33.65 (5.8) | 33.6 (4) | 0.986b |
| LDH (U/L) | 290 (143) | 188 (34) | < 0.001b | 245 (110) | 193 (48) | < 0.001b | 290 (143) | 245 (110) | 0.001b |
| ALP (IU/L) | 114 (49) | 113.5 (43) | 0.631b | 127 (57) | 120 (67) | 0.090b | 114 (49) | 127 (57) | 0.001b |
| Creatinine (mg/dL) | 0.60 (0.21) | 0.48 (0.13) | < 0.001b | 0.59 (0.17) | 0.51 (0.13) | < 0.001b | 0.60 (0.21) | 0.59 (0.17) | 0.892b |
| Uric acid (mg/dL) | 5.8 (2.5) | 3.7 (1) | < 0.001b | 5.4 (1.9) | 3.70 (1.2) | < 0.001b | 5.8 (2.5) | 5.4 (1.9) | 0.727b |
| Fibrinogen (mg/dL) | 484 (137) | 481 (112) | 0.443b | 499.5 (116) | 470.5 (96) | 0.008b | 484 (137) | 499.5 (116) | 0.060b |
| TSH (mU/mL) | 2.26 (1.52) | 1.91 (1.33) | 0.006b | 23 (1.38) | 1.9 (1.43) | 0.360b | 2.26 (1.52) | 23 (1.38) | 0.175b |
| 24-hour urine protein (mg) | 572 (1792.5) | - | N/A | 467 (481) | − | N/A | 572 (1792.5) | 467 (481) | 0.009b |
Data are expressed as n (%), mean ± SD or median (IQR) where appropriate. A p value of < 0.05 indicates a significant difference and statistically significant p-values are in bold. EO-PE Early onset preeclampsia; LO-PE Late onset preeclampsia; BMI Body mass index; ASA Acetylsalicylic acid; UA-SD Umbilical artery systolic/diastolic ratio; UA-PI Umbilical artery pulsatility index; AST Aspartate aminotransferase; ALT Alanine aminotransferase; LDH Lactate dehydrogenase; ALP Alkaline phosphatase; TSH Thyroid stimulating hormone. a: Student’s T-test, b: Mann-Whitney U test, c: Pearson Chi-square test, d: Fisher’s Exact test
Table 2 presents the maternal and neonatal outcomes of EO-PE, LO-PE, and control groups. Thrombocytopenia was observed in 12.9% of patients with EO-PE and 6.0% of those with LO-PE, with no cases in either control group (p < 0.001 for EO-PE vs. control, p = 0.002 for LO-PE vs. control, and p = 0.036 for EO-PE vs. LO-PE). Renal dysfunction was recorded in 9.4% of EO-PE and 4.0% of LO-PE cases, with no reported cases in controls (p < 0.001 and p = 0.013, respectively). Hepatic dysfunction occurred in 10.5% of EO-PE and 5.3% of LO-PE cases, while no such findings were reported in the control groups (p < 0.001 and p = 0.004, respectively). HELLP syndrome was identified in 11.1% of EO-PE cases and 2.6% of LO-PE cases, with no occurrences in controls (p < 0.001 for EO-PE vs. control, p = 0.044 for LO-PE vs. control, p = 0.003 for EO-PE vs. LO-PE). Eclampsia was diagnosed in 6.4% of EO-PE and 1.4% of LO-PE patients, while it was absent in the control groups (p < 0.001, p = 0.155, and p = 0.020, respectively). Maternal ICU admission was significantly more frequent in EO-PE (8.2%) compared to LO-PE (1.7%) (p = 0.013), and was not reported in either control group (p < 0.001). DIC occurred in 2.9% of EO-PE and 0.6% of LO-PE cases, and pulmonary edema was seen in 1.2% of EO-PE patients, with no cases documented in LO-PE and control groups. Maternal mortality was not observed in any of the study groups. CAMO were significantly higher in EO-PE (30.6%) than in LO-PE (19.3%, p < 0.028) and controls (0%, p < 0.001). The gestational age at delivery was significantly lower in the EO-PE group (median: 34 weeks) compared to controls (median: 39 weeks, p < 0.001). Similarly, LO-PE cases delivered significantly earlier than their controls (median: 37 weeks vs. 39 weeks, p < 0.001). The rate of preterm birth was highest in the EO-PE group (72.9%), significantly higher than both the control group (14.2%, p < 0.001) and the LO-PE group (32.7%, p < 0.001). The cesarean section rate was highest in EO-PE (85.3%) compared to controls (50.3%, p < 0.001) and LO-PE (72%, p = 0.004). Newborns in the EO-PE group had significantly lower birth weights (1988 ± 904 g) compared to both the LO-PE group (2748 ± 527 g, p < 0.001) and the control group (3153 ± 455 g, p < 0.001). Birth weight was also significantly lower in LO-PE compared to controls (p < 0.001). Apgar scores at both 1 and 5 min were significantly lower in EO-PE neonates compared to both LO-PE and controls (p < 0.001, for all). Neonatal intensive care unit (NICU) admission was also significantly more frequent in EO-PE (61.3%) compared to LO-PE (23.3%, p < 0.001) and controls (9.7%, p < 0.001). CANO were significantly higher in EO-PE (64.1%) than in LO-PE (24%, p < 0.001) and controls (10.3%, p < 0.001). Intrauterine fetal demise (IUFD) occurred in 4.1% of EO-PE cases, which was significantly higher than in LO-PE (1.3%, p = 0.015) and absent in controls (0%, p < 0.001).
Table 2.
Maternal and neonatal outcomes of EO-PE, LO-PE, and control groups
| EO-PE n = 170 (27.2%) |
Control n = 155 (48.8%) |
p value | LO-PE n = 150 (50%) |
Control n = 150 (50%) |
p value | EO-PE n = 170 (53.1%) |
LO-PE n = 150 (46.9%) |
p value | |
|---|---|---|---|---|---|---|---|---|---|
| Thrombocytopenia | 22 (12.9%) | 0 (0%) | < 0.001d | 9 (6.0%) | 0 (0%) | 0.002d | 22 (12.9%) | 9 (6.0%) | 0.036b |
| Renal dysfunction | 16 (9.4%) | 0 (0%) | < 0.001d | 6 (4.0%) | 0 (0%) | 0.013d | 16 (9.4%) | 6 (4.0%) | 0.056b |
| Hepatic dysfunction | 18 (10.5%) | 0 (0%) | < 0.001d | 8 (5.3%) | 0 (0%) | 0.004d | 18 (10.5%) | 8 (5.3%) | 0.085b |
| HELLP syndrome | 19 (11.1%) | 0 (0%) | < 0.001d | 4 (2.6%) | 0 (0%) | 0.044d | 19 (11.1%) | 4 (2.6%) | 0.003d |
| Disseminated intravascular coagulation (DIC) | 5 (2.9%) | 0 (0%) | 0.031d | 1 (0.6%) | 0 (0%) | 0.316d | 5 (2.9%) | 1 (0.6%) | 0.134d |
| Pulmonary edema | 2 (1.2%) | 0 (0%) | 0.175d | 0 (0%) | 0 (0%) | N/A | 2 (1.2%) | 0 (0%) | 0.182d |
| Eclampsia | 11 (6.4%) | 0 (0%) | < 0.001d | 2 (1.4%) | 0 (0%) | 0.155d | 11 (6.4%) | 2 (1.4%) | 0.020d |
| Maternal ICU admission | 14 (8.2%) | 0 (0%) | < 0.001d | 3 (1.7%) | 0 (0%) | 0.081d | 14 (8.2%) | 3 (1.7%) | 0.013d |
| Maternal mortality | 0 (0%) | 0 (0%) | N/A | 0 (0%) | 0 (0%) | N/A | 0 (0%) | 0 (0%) | N/A |
| CAMO* | 52 (30.6%) | 0 (0%) | < 0.001d | 29 (19.3%) | 0 (0%) | < 0.001 d | 52 (30.6%) | 29 (19.3%) | < 0.028b |
| Gestational age at delivery (week) | 34 (5) | 39 (2) | < 0.001a | 37 (2) | 39 (2) | < 0.001a | 34 (5) | 37 (2) | < 0.001a |
| Preterm birth (< 37 week) | 124 (72.9%) | 22 (14.2%) | < 0.001b | 49 (32.7%) | 13 (8.7%) | < 0.001b | 124 (72.9%) | 49 (32.7%) | < 0.001b |
| Birth weight (gram) | 1988 ± 904 | 3153 ± 455 | 0.001c | 2748 ± 527 | 3174 ± 407 | 0.001c | 1988 ± 904 | 2748 ± 527 | 0.001c |
| Cesarean section | 145 (85.3%) | 78 (50.3%) | < 0.001b | 108 (72%) | 91 (60.7%) | 0.038b | 145 (85.3%) | 108 (72%) | 0.004b |
| FGR | 60 (35.3%) | 0 (0%) | < 0.001d | 29 (19.3%) | 0 (0%) | < 0.001d | 60 (35.3%) | 29 (19.3%) | 0.001b |
| Corticosteroid treatment | 140 (82.4%) | 17 (11.0%) | < 0.001b | 70 (47%) | 12 (8.1%) | < 0.001b | 140 (82.4%) | 70 (47%) | < 0.001b |
| Premature rupture of membranes | 9 (5.3%) | 4 (2.6%) | 0.264d | 9 (6%) | 3 (2%) | 0.138d | 9 (5.3%) | 9 (6%) | 0.784b |
| Placental abruption | 8 (4.7%) | 0 (0%) | 0.008d | 1 (0.7%) | 0 (0%) | 1d | 8 (4.7%) | 1 (0.7%) | 0.040d |
| Umbilical cord pH | 7.31 (0.13) | 7.42 (0.02) | 0.017a | 7.37 (0.12) | 7.36 (0.33) | 0.302a | 7.31 (0.13) | 7.37 (0.12) | 0.008a |
| Transient tachypnea of the newborn | 36 (21.8%) | 8 (5.2%) | < 0.001b | 16 (10.7%) | 9 (6%) | 0.144b | 36 (21.8%) | 16 (10.7%) | 0.008b |
| Respiratory distress syndrome | 66 (40%) | 3 (1.9%) | < 0.001d | 13 (8.7%) | 3 (2%) | 0.018d | 66 (40%) | 13 (8.7%) | < 0.001b |
| Continues positive airway pressure | 70 (42.4%) | 8 (5.2%) | < 0.001b | 16 (10.7%) | 14 (9.3%) | 0.700b | 70 (42.4%) | 16 (10.7%) | < 0.001b |
| Mechanical ventilation | 44 (26.7%) | 2 (1.3%) | < 0.001d | 7 (4.7%) | 4 (2.7%) | 0.541d | 44 (26.7%) | 7 (4.7%) | < 0.001b |
| Phototherapy for neonates | 23 (13.9%) | 6 (3.9%) | 0.002b | 16 (10.7%) | 6 (4%) | 0.027b | 23 (13.9%) | 16 (10.7%) | 0.378b |
| Neonatal hypoglycemia | 13 (7.9%) | 2 (1.3%) | 0.007d | 9 (6%) | 2 (1.3%) | 0.061d | 13 (7.9%) | 9 (6%) | 0.659b |
| Interventricular hemorrhage | 3 (1.8%) | 2 (1.3%) | 1d | 0 (0%) | 0 (0%) | N/A | 3 (1.8%) | 0 (0%) | 0.249d |
| Necrotizing enterocolitis | 1 (0.6%) | 0 (0%) | 1d | 0 (0%) | 0 (0%) | N/A | 1 (0.6%) | 0 (0%) | 1d |
| Neonatal sepsis | 9 (5.5%) | 0 (0%) | 0.004d | 2 (1.3%) | 0 (0%) | 0.498d | 9 (5.5%) | 2 (1.3%) | 0.064d |
| Apgar score at 1 st minute | 8 (3) | 9 (0) | < 0.001a | 9 (1) | 9 (0) | 0.001a | 8 (3) | 9 (1) | 0.001a |
| Apgar score at 5th minute | 9 (3) | 10 (0) | < 0.001a | 10 (1) | 10 (0) | 0.001a | 9 (3) | 10 (1) | 0.001a |
| NICU admission | 103 (61.3%) | 15 (9.7%) | < 0.001b | 35 (23.3%) | 19 (12.7%) | 0.016b | 103 (61.3%) | 35 (23.3%) | < 0.001b |
| CANO** | 109 (64.1%) | 16 (10.3%) | < 0.001b | 36 (24%) | 22 (14.7%) | 0.041b | 109 (64.1%) | 36 (24%) | < 0.001b |
| Intrauterine fetal demise | 7 (4.1%) | 0 (0%) | 0.015d | 2 (1.3%) | 0 (0%) | 0.498d | 7 (4.1%) | 2 (1.3%) | 0.181d |
Data are expressed as n (%), mean ± SD or median (IQR) where appropriate. A p value of < 0.05 indicates a significant difference and statistically significant p-values are in bold. EO-PE Early onset preeclampsia; LO-PE Late onset preeclampsia; HELLP Hemolysis, elevated liver enzmymes, low platelet; FGR Fetal growth restriction; NICU Neonatal intensive care unit; CAMO Composite adverse maternal outcome; CANO Composite adverse neonatal outcome. a: Mann-Whitney U test, b: Pearson Chi-square, c: Student’s T-test, d: Fisher’s Exact test
* CAMO: Composite adverse maternal outcomes include the presence of at least one of the following adverse outcomes: thrombocytopenia, renal dysfunction, hepatic dysfunction, HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), disseminated intravascular coagulation (DIC), pulmonary edema, eclampsia, and admission to the maternal intensive care unit (ICU)
** CANO: Composite adverse neonatal outcomes include the presence of at least one of the following adverse outcomes: transient tachypnea of the newborn, respiratory distress syndrome, need for continuous positive airway pressure, need for mechanical ventilation, need for phototherapy, neonatal hypoglycemia, intraventricular hemorrhage, necrotizing enterocolitis, neonatal sepsis, 5th minute APGAR score < 7, neonatal intensive care unit (NICU) admission, placental abruption, and preterm birth
Table 3 presents a comparison of inflammatory and metabolic indices among EO-PE, LO-PE, and control groups. The uric acid/albumin ratio was significantly elevated in EO-PE and LO-PE compared to controls (adjusted p < 0.001, for both), with no significant difference between EO-PE and LO-PE. Conversely, the fibrinogen/uric acid ratio was significantly lower in EO-PE and LO-PE compared to controls (adjusted p = 0.002 and p < 0.001, respectively), while no significant difference was found between EO-PE and LO-PE. The uric acid/creatinine ratio was significantly higher in both the EO-PE and LO-PE groups compared to controls (adjusted p = 0.012 and p < 0.001, respectively), although no significant difference was observed between EO-PE and LO-PE. The creatinine/body weight ratio did not significantly differ between EO-PE and control, or between LO-PE and control, and showed no significant difference between EO-PE and LO-PE. The AST/ALT ratio did not differ significantly between EO-PE and controls or between LO-PE and controls, but it was significantly lower in EO-PE than in LO-PE (p = 0.006). Similarly, the AST/PLT ratio was significantly higher in EO-PE and LO-PE compared to controls (adjusted p = 0.015 and p < 0.001, respectively), but no significant difference was observed between EO-PE and LO-PE. FIB-4 was significantly elevated in EO-PE and LO-PE compared to controls (adjusted p = 0.021 and p < 0.001, respectively), while no difference was observed between EO-PE and LO-PE. Meanwhile, FIB-5 was significantly lower in EO-PE compared to controls (adjusted p = 0.017), whereas no significant difference was found between LO-PE and controls or between EO-PE and LO-PE.
Table 3.
Comparison of inflammatory and metabolic indices in the EO-PE, LO-PE, and control groups
| EO-PE n = 170 (47.7%) |
Control n = 155 (52.3%) |
p value | Adjusted p value* | LO-PE n = 150 (50%) |
Control n = 150 (50%) |
p value | Adjusted p value* | EO-PE n = 170 (53.1%) |
LO-PE n = 150 (46.9%) |
p value | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Uric acid/Albumin ratio | 0.1682 (0.1047) | 0.0997 (0.0293) | < 0.001a | < 0.001 | 0.1608 (0.0666) | 0.0973 (0.0339) | < 0.001a | < 0.001 | 0.1682 (0.1047) | 0.1608 (0.0666) | 0.730a |
| Fibrinogen/Uric acid ratio | 84.37 (51.43) | 125.56 (45.93) | < 0.001a | 0.002 | 93.76 (37.29) | 127.22 (51.81) | < 0.001a | < 0.001 | 84.37 (51.43) | 93.76 (37.29) | 0.186a |
| Uric acid/Creatinine ratio | 8.79 (3.54) | 7.69 (2.84) | < 0.001a | 0.012 | 9.11 (3.32) | 7.06 (3.46) | < 0.001a | < 0.001 | 8.79 (3.54) | 9.11 (3.32) | 0.316a |
| Creatinin/Body weight ratio | 0.0083 (0.0044) | 0.0077 (0.0025) | 0.092a | - | 0.0078 (0.0031) | 0.0078 (0.0034) | 0.593a | - | 0.0083 (0.0044) | 0.0078 (0.0031) | 0.467a |
| AST/PLT ratio | 0.0849 (0.0765) | 0.0625 (0.0329) | < 0.001a | 0.015 | 0.0812 (0.0655) | 0.0628 (0.0389) | < 0.001a | < 0.001 | 0.0849 (0.0765) | 0.0812 (0.0655) | 0.335a |
| AST/ALT ratio | 1.43 (0.77) | 1.5 (0.75) | 0.098a | - | 1.63 (0.67) | 1.56 (0.67) | 0.106a | - | 1.43 (0.77) | 1.63 (0.67) | 0.006a |
| FIB 4 | 0.7228 (0.5648) | 0.5757 (0.3195) | < 0.001a | 0.021 | 0.7047 (0.5704) | 0.5409 (0.3211) | < 0.001a | < 0.001 | 0.7228 (0.5648) | 0.7047 (0.5704) | 0.754a |
| FIB 5 | 43.27 (6.5) | 45.32 (8.09) | 0.009a | 0.017 | 44.47 (7.04) | 45.26 (5.83) | 0.526a | - | 43.27 (6.5) | 44.47 (7.04) | 0.121a |
Data are expressed as n (%) or median (IQR) where appropriate. A p value of < 0.05 indicates a significant difference and statistically significant p-values are in bold. EO-PE Early onset preeclampsia; LO-PE Late onset preeclampsia; AST Aspartate aminotransferase; ALT Alanine aminotransferase; PLT Platelet count; FIB 4 Fibrosis 4 index; FIB 5 Fibrosis 5 index, a: Mann-Whitney U test
* Adjusted p-values were calculated using logistic regression models controlling for maternal age and body mass index (BMI)
The associations between inflammatory and metabolic indices and the presence of EO-PE and LO-PE is presented in Table 4. Among the biomarkers analyzed, the uric acid/albumin ratio demonstrated the highest discriminative accuracy for both EO-PE and LO-PE. In EO-PE, it had an AUC of 0.831 (95% CI: 0.79–0.88, p < 0.001), with a sensitivity of 77.6% and a specificity of 79.4% at a cut-off of > 0.1170. Similarly, in LO-PE, the uric acid/albumin ratio had an AUC of 0.888 (95% CI: 0.85–0.93, p < 0.001), a sensitivity of 83.3%, and a specificity of 81.3% at a cut-off of > 0.1222, making it the most effective biomarker for both conditions. The fibrinogen/uric acid ratio also demonstrated strong discriminative value, with an AUC of 0.752 (95% CI: 0.69–0.81, p < 0.001) in EO-PE and 0.775 (95% CI: 0.72–0.83, p < 0.001) in LO-PE. The optimal cut-off values for EO-PE and LO-PE were < 111.85 and < 111.33, respectively. Additionally, the uric acid/creatinine ratio showed discriminative ability, with an AUC of 0.663 (95% CI: 0.60–0.72, p < 0.001) in EO-PE and 0.716 (95% CI: 0.66–0.77, p < 0.001) in LO-PE. Other biomarkers such as the AST/PLT ratio and FIB-4 showed modest discriminative value, with AUCs of 0.686 and 0.669, respectively, in EO-PE, and 0.646 and 0.641, respectively, in LO-PE. The FIB-5 index had the lowest discriminative power, with an AUC of 0.603 (95% CI: 0.53–0.68, p = 0.009) in EO-PE and was not diagnostic in LO-PE. The creatinine/body weight ratio and AST/ALT ratio were not diagnostic of EO-PE or LO-PE (Fig. 2).
Table 4.
Association of inflammatory and metabolic indices with EO-PE and LO-PE status
| LR+ | LR- | Cut-off * | Sensitivity | Specificity | AUC | %95 CI | P-value | |
|---|---|---|---|---|---|---|---|---|
| EO-PE group | ||||||||
| Uric acid/Albumin ratio | 3.77 | 0.28 | > 0.1170 | 77.6% | 79.4% | 0.831 | 0.79–0.88 | < 0.001 |
| Fibrinogen/Uric acid ratio | 2.29 | 0.44 | < 111.85 | 69.5% | 69.7% | 0.752 | 0.69–0.81 | < 0.001 |
| Uric acid/Creatinine ratio | 1.69 | 0.61 | > 8.21 | 61.2% | 63.9% | 0.663 | 0.60–0.72 | < 0.001 |
| AST/PLT ratio | 1.62 | 0.63 | > 0.0694 | 60.6% | 62.6% | 0.686 | 0.63–0.74 | < 0.001 |
| FIB 4 | 1.84 | 0.59 | > 0.6297 | 60.6% | 67.1% | 0.669 | 0.61–0.73 | < 0.001 |
| FIB 5 | 1.35 | 0.76 | < 44.21 | 54.9% | 59.4% | 0.603 | 0.53–0.68 | 0.009 |
| LO-PE group | ||||||||
| Uric acid/Albumin ratio | 4.46 | 0.20 | > 0.1222 | 83.3% | 81.3% | 0.888 | 0.85–0.93 | < 0.001 |
| Fibrinogen/Uric acid ratio | 2.5 | 0.42 | < 111.33 | 70% | 72% | 0.775 | 0.72–0.83 | < 0.001 |
| Uric acid/Creatinine ratio | 2.07 | 0.51 | > 8.51 | 64.7% | 68.7% | 0.716 | 0.66–0.77 | < 0.001 |
| AST/PLT ratio | 1.55 | 0.65 | > 0.0725 | 60% | 61.3% | 0.646 | 0.58–0.71 | < 0.001 |
| FIB 4 | 1.53 | 0.65 | > 0.6045 | 61.3% | 60% | 0.641 | 0.58–0.71 | < 0.001 |
* Cut-off values were found according to Youden index. LR+ Positive likelihood ratio; LR- Negative likelihood ratio; AUC Area under the curve; CI Confidence interval; AST Aspartate aminotransferase; PLT Platelet count; FIB 4 Fibrosis 4 index; FIB 5 Fibrosis 5 index
Fig. 2.
The ROC curves for differentiating EO-PE and LO-PE from control groups
The predictive performance of inflammatory and metabolic indices for identifying CAMO in EO-PE and LO-PE groups is presented in Table 5. In the EO-PE group, the uric acid/albumin ratio demonstrated the highest predictive value for CAMO, with an AUC of 0.701 (95% CI: 0.61–0.78, p = 0.001), a sensitivity of 68.6%, and a specificity of 62.4% at a cut-off value of > 0.1299. The fibrinogen/uric acid ratio also showed significant predictive performance (AUC: 0.647, 95% CI: 0.54–0.73, p = 0.004). Additionally, both the AST/PLT ratio (AUC: 0.645, p = 0.002) and FIB-4 (AUC: 0.632, p = 0.004) were associated with CAMO in EO-PE cases. In the LO-PE group, the uric acid/albumin ratio was again the most predictive marker, with an AUC of 0.788 (95% CI: 0.70–0.87, p = 0.001), a sensitivity of 74.5%, and a specificity of 74.0% at a cut-off of > 0.0922. The fibrinogen/uric acid ratio (AUC: 0.714, p < 0.001), FIB-4 (AUC: 0.688, p < 0.001), and AST/PLT ratio (AUC: 0.681, p = 0.003) also demonstrated significant predictive value in this group (Fig. 3).
Table 5.
The predictive performance of inflammatory and metabolic indices for prediction of CAMO in EO-PE and LO-PE groups
| LR+ | LR- | Cut-off * | Sensitivity | Specificity | AUC | %95 CI | P-value | |
|---|---|---|---|---|---|---|---|---|
| EO-PE Group | ||||||||
| Uric acid/Albumin ratio | 1.82 | 0.51 | > 0.1299 | 68.6% | 62.4% | 0.701 | 0.61–0.78 | 0.001 |
| Fibrinogen/Uric acid ratio | 1.58 | 0.61 | < 91.82 | 63.7% | 59.6% | 0.647 | 0.54–0.73 | 0.004 |
| Uric acid/Creatinine ratio | 1.29 | 0.76 | > 8.28 | 58.8% | 54.4% | 0.598 | 0.51–0.68 | 0.031 |
| Creatinine/Body weight ratio | - | - | - | - | - | - | - | 0.155 |
| AST/PLT ratio | 1.52 | 0.63 | > 0.0736 | 62.7% | 58.8% | 0.645 | 0.55–0.73 | 0.002 |
| AST/ALT ratio | - | - | - | - | - | - | - | 0.809 |
| FIB 4 | 1.49 | 0.66 | > 0.6720 | 60.8% | 59.1% | 0.632 | 0.54–0.72 | 0.004 |
| FIB 5 | - | - | - | - | - | - | - | 0.911 |
| LO-PE group | ||||||||
| Uric acid/Albumin ratio | 2.87 | 0.34 | > 0.0922 | 74.5% | 74.0% | 0.788 | 0.70–0.87 | 0.001 |
| Fibrinogen/Uric acid ratio | 1.47 | 0.68 | < 104.15 | 60.1% | 59.0% | 0.714 | 0.60–0.81 | < 0.001 |
| Uric acid/Creatinine ratio | - | - | - | - | - | - | - | 0.347 |
| Creatinine/Body weight ratio | - | - | - | - | - | - | - | 0.141 |
| AST/PLT ratio | 1.41 | 0.71 | > 0.0777 | 58.6% | 58.3% | 0.681 | 0.58–0.78 | 0.003 |
| AST/ALT ratio | - | - | - | - | - | - | - | 0.973 |
| FIB 4 | 1.45 | 0.66 | > 0.6540 | 62.1% | 57.2% | 0.688 | 0.57–0.78 | < 0.001 |
| FIB 5 | - | - | - | - | - | - | - | 0.296 |
* Cut-off values were found according to Youden index. LR+ Positive likelihood ratio; LR- Negative likelihood ratio; AUC Area under the curve; CI Confidence interval; AST Aspartate aminotransferase; ALT Alanine aminotransferase; PLT Platelet count; FIB 4 Fibrosis 4 index; FIB 5 Fibrosis 5 index
Fig. 3.
The ROC curves for predicting CAMO in the EO-PE and LO-PE groups
The predictive performance of inflammatory and metabolic indices for prediction of CANO in EO-PE and LO-PE groups is presented in Table 6. Among the biomarkers analyzed, the uric acid/albumin ratio demonstrated the highest predictive accuracy for CANO in EO-PE, with an AUC of 0.831, a sensitivity of 68%, and a specificity of 80% at a cut-off value of > 0.1388 (p < 0.001). The fibrinogen/uric acid ratio also showed strong predictive value, with an AUC of 0.733 (95% CI: 0.67–0.80, p < 0.001), a sensitivity of 68.2%, and a specificity of 70.5% at a cut-off of < 104.09. Other biomarkers, including the creatinine/body weight ratio (AUC: 0.651, p < 0.001), uric acid/creatinine (AUC: 0.627, p < 0.001) ratio, AST/PLT ratio (AUC: 0.686, p < 0.001), FIB-4 (AUC: 0.669, p < 0.001), and FIB-5 (AUC: 0.629, p = 0.001) exhibited moderate predictive value for CANO in EO-PE. In the LO-PE group, the fibrinogen/uric acid ratio emerged as the strongest predictor of CANO, with an AUC of 0.775 (95% CI: 0.72–0.83, p < 0.001), a sensitivity of 70%, and a specificity of 72% at a cut-off of < 111.33. The uric acid/albumin ratio (AUC: 0.606, p = 0.012) and the uric acid/creatinine ratio (AUC: 0.586, p = 0.042) also demonstrated predictive value for CANO in LO-PE (Fig. 4).
Table 6.
The predictive performance of inflammatory and metabolic indices for prediction of CANO in EO-PE and LO-PE groups
| LR+ | LR- | Cut-off * | Sensitivity | Specificity | AUC | %95 CI | P-value | |
|---|---|---|---|---|---|---|---|---|
| EO-PE group | ||||||||
| Uric acid/Albumin ratio | 3.4 | 0.28 | > 0.1388 | 68% | 80% | 0.831 | 0.70–0.82 | < 0.001 |
| Fibrinogen/Uric acid ratio | 2.31 | 0.44 | < 104.09 | 68.2% | 70.5% | 0.733 | 0.67–0.80 | < 0.001 |
| Uric acid/Creatinine ratio | 1.72 | 0.62 | > 8.55 | 59.2% | 65.5% | 0.627 | 0.56–0.69 | < 0.001 |
| Creatinine/Body weight ratio | 2.05 | 0.54 | > 0.0082 | 62.4% | 69.5% | 0.651 | 0.59–0.71 | < 0.001 |
| AST/PLT ratio | 1.71 | 0.6 | > 0.0728 | 61.6% | 64% | 0.686 | 0.62–0.74 | < 0.001 |
| AST/ALT ratio | - | - | - | - | - | - | - | 0.072 |
| FIB 4 | 1.5 | 0.68 | > 0.6425 | 58.4% | 61% | 0.669 | 0.55–0.68 | < 0.001 |
| FIB 5 | 1.76 | 0.65 | < 44.35 | 55.3% | 68.6% | 0.629 | 0.56–0.70 | 0.001 |
| LO-PE group | ||||||||
| Uric acid/Albumin ratio | 1.50 | 0.65 | > 0.1289 | 62.1% | 58.7% | 0.606 | 0.52–0.69 | 0.012 |
| Fibrinogen/Uric acid ratio | 2.5 | 0.42 | < 111.33 | 70% | 72% | 0.775 | 0.72–0.83 | < 0.001 |
| Uric acid/Creatinine ratio | 1.30 | 0.77 | > 8.57 | 56.9% | 56.2% | 0.586 | 0.50–0.67 | 0.042 |
| Creatinine/Body weight ratio | - | - | - | - | - | - | - | 0.584 |
| AST/PLT ratio | - | - | - | - | - | - | - | 0.061 |
| AST/ALT ratio | - | - | - | - | - | - | - | 0.935 |
| FIB 4 | - | - | - | - | - | - | - | 0.077 |
| FIB 5 | - | - | - | - | - | - | - | 0.225 |
* Cut-off values were found according to Youden index. LR+ Positive likelihood ratio; LR- Negative likelihood ratio; AUC Area under the curve; CI Confidence interval; AST Aspartate aminotransferase; ALT Alanine aminotransferase; PLT Platelet count; FIB 4 Fibrosis 4 index; FIB 5 Fibrosis 5 index
Fig. 4.
The ROC curves for predicting CANO in the EO-PE and LO-PE groups
The associations between inflammatory and metabolic indices with preeclampsia severity are presented in Table 7. Among the biomarkers analyzed, the uric acid/albumin ratio exhibited the highest discriminative accuracy, with an AUC of 0.708 (95% CI: 0.65–0.77, p < 0.001), a sensitivity of 68.4%, and a specificity of 64% at a cut-off value of > 0.1631. The creatinine/body weight ratio (AUC: 0.672, p < 0.001), fibrinogen/uric acid ratio (AUC: 0.669, p < 0.001), AST/PLT ratio (AUC: 0.623, p < 0.001), uric acid/creatinine ratio (AUC: 0.568, p < 0.037), FIB-4 (AUC: 0.569, p = 0.033), and FIB-5 (AUC: 0.591, p = 0.010) also demonstrated discriminative value (Fig. 5).
Table 7.
Association of inflammatory and metabolic indices with preeclampsia severity
| LR+ | LR- | Cut-off * | Sensitivity | Specificity | AUC | %95 CI | P-value | |
|---|---|---|---|---|---|---|---|---|
| Uric acid/Albumin ratio | 1.9 | 0.49 | > 0.1631 | 68.4% | 64% | 0.708 | 0.65–0.77 | < 0.001 |
| Fibrinogen/Uric acid ratio | 1.79 | 0.61 | < 93.84 | 59.3% | 66.9% | 0.669 | 0.60–0.73 | < 0.001 |
| Uric acid/Creatinine ratio | 1.30 | 0.77 | > 9.02 | 56.1% | 56.7% | 0.568 | 0.50–0.63 | 0.037 |
| Creatinine/Body weight ratio | 1.76 | 0.61 | > 0.0084 | 60% | 65.9% | 0.672 | 0.61–0.73 | < 0.001 |
| AST/PLT ratio | 1.48 | 0.68 | > 0.0837 | 59.4% | 59.8% | 0.623 | 0.56–0.68 | < 0.001 |
| AST/ALT ratio | - | - | - | - | - | - | - | 0.614 |
| FIB 4 | 1.23 | 0.81 | > 0.7189 | 54.8% | 55.5% | 0.569 | 0.51–0.63 | 0.033 |
| FIB 5 | 1.37 | 0.65 | < 42.75 | 66.7% | 51.4% | 0.591 | 0.52–0.66 | 0.010 |
* Cut-off values were found according to Youden index; LR+ Positive likelihood ratio; LR- Negative likelihood ratio; AUC Area under the curve; CI Confidence interval; AST Aspartate aminotransferase; ALT Alanine aminotransferase; PLT Platelet count; FIB 4 Fibrosis 4 index; FIB 5 Fibrosis 5 index
Fig. 5.
The ROC curves for predicting disease severity in all preeclampsia patients
Discussion
In this study, we comprehensively evaluated the clinical utility and prognostic usefulness of various inflammatory and metabolic indices indicating systemic vascular dysfunction and organ damage in patients with preeclampsia, including uric acid/albumin ratio, fibrinogen/uric acid ratio, uric acid/creatinine ratio, creatinine/body weight ratio, AST/ALT ratio, AST/PLT ratio, FIB-4, and FIB-5. Our findings identified the uric acid/albumin ratio and fibrinogen/uric acid ratio as the most strongly associated with both EO-PE and LO-PE. Notably, the uric acid/albumin ratio demonstrated the highest discriminative accuracy, with an AUC of 0.831 for EO-PE and 0.888 for LO-PE, while the fibrinogen/uric acid ratio also exhibited a strong discriminative value, with an AUC of 0.752 in EO-PE and 0.775 in LO-PE. Beyond their discriminative roles, these indices were also exhibited significant prediction of CAMO and CANO. In the prediction of CAMO, the uric acid/albumin ratio (AUC: 0.701) and fibrinogen/uric acid ratio (AUC: 0.647) were the top-performing markers in EO-PE, while in LO-PE, the uric acid/albumin ratio (AUC: 0.788) and fibrinogen/uric acid ratio (AUC: 0.714) demonstrated the highest predictive value. In the EO-PE group, the uric acid/albumin ratio (AUC: 0.831) and the fibrinogen/uric acid ratio (AUC: 0.733) were most strongly associated with CANO, whereas in the LO-PE group, the fibrinogen/uric acid ratio (AUC: 0.775) and the uric acid/albumin ratio (AUC: 0.606) had the highest associated. Additionally, these markers were linked with severe preeclampsia, with the uric acid/albumin ratio (AUC: 0.708), creatinine/body weight ratio (AUC: 0.672), and fibrinogen/uric acid ratio (AUC: 0.669) ranking among the most reliable markers. These results suggest that both indices could be valuable not only for discriminative preeclampsia but also for predicting its severity and associated maternal-fetal complications.
Preeclampsia is a systemic disease characterized by inflammation, oxidative stress, and endothelial dysfunction. Hyperuricemia is a hallmark of preeclampsia, resulting from renal dysfunction, reduced glomerular filtration rate, and increased oxidative stress [17]. On the other hand, decreased albumin levels are associated with increased vascular permeability, inflammation, and hepatic dysfunction [18]. Therefore, elevated uric acid/albumin ratio has been considered as an important biomarker of disease severity and vascular damage. Previous studies have showed that hyperuricemia and hypoalbuminemia are directly related to the severity of the disease in patients with preeclampsia and our findings support this literature [19, 20]. However, only one study in the literature has evaluated the relationship between the uric acid/albumin ratio and preeclampsia severity. In a study by Mohamed et al., which included 45 preeclamptic patients, no significant differences were found in uric acid, albumin, or the uric acid/albumin ratio between mild and severe preeclampsia groups [21]. In contrast, our study demonstrated that the uric acid/albumin ratio had the highest AUC values for differentiating preeclampsia, identifying CAMO, and assessing disease severity in both EO-PE and LO-PE cases. While it was among the top indices associated with CANO in EO-PE, it showed modest predictive performance for CANO in LO-PE. There are several possible explanations for these discrepancies. First, our study included a larger sample size and separately analyzed EO-PE and LO-PE cases, whereas Mohamed et al.‘s study had only 45 patients (23 with mild and 22 with severe preeclampsia), and did not differentiate EO-PE from LO-PE. The small sample size in their study may have limited statistical power and subgroup analyses, leading to different conclusions. Second, Mohamed et al.‘s study did not specify the exact timing of blood sampling in relation to the onset of preeclampsia. The variations in the timing of blood sampling and laboratory reference ranges could introduce additional variability, as uric acid and albumin levels fluctuate throughout pregnancy. Third, they did not exclude women with chronic hypertension, a condition that may increase baseline uric acid levels, thereby affecting the uric acid/albumin ratio. Additionally, variations in ethnic backgrounds, nutritional status, and maternal metabolic profiles could also contribute to differences in findings.
The fibrinogen/uric acid ratio is considered an indicator of coagulation activation and inflammation in preeclampsia. As a result of endothelial damage, microvascular thrombosis, and a tendency for DIC, fibrinogen levels increase in preeclamptic patients [22]. However, it is also hypothesized that fibrinogen consumption increases due to hyperfibrinolysis in progressive disease states, which may lead to variability in the direct relationship between fibrinogen levels and disease severity [8]. On the other hand, the significant increase in uric acid levels reflects renal dysfunction and oxidative stress, underscoring the importance of the fibrinogen/uric acid ratio in disease progression [23]. In the literature, only one study has investigated this ratio in preeclampsia, focusing on its role in predicting fetal growth restriction (FGR). Nori et al. reported a positive correlation between the fibrinogen/uric acid ratio and fetal growth parameters and the amniotic fluid index (AFI), while an inverse correlation with blood pressure was observed [24]. Our findings further support the role of fibrinogen/uric acid ratio in preeclampsia presence, severity, and adverse maternal-fetal outcomes. We observed that this ratio was significantly lower in patients with severe preeclampsia compared to mild cases, suggesting increased fibrinogen consumption in progressive disease states. Additionally, our study showed that the fibrinogen/uric acid ratio was one of the indicators of CAMO and CANO in both EO-PE and LO-PE cases.
The uric acid to creatinine ratio is a significant biomarker used in various medical assessments, particularly in relation to metabolic disorders, cardiovascular health, and renal function [25–27]. It is a useful predictor of renal dysfunction, especially in diabetic patients, and has been shown to correlate with the progression of chronic kidney disease in Type 2 DM patients, making it an important tool for assessing renal health and predicting disease progression [25]. In preeclampsia, increased systemic vascular resistance and decreased renal blood flow contribute to hyperuricemia and irregularities in creatinine metabolism. This is particularly evident in EO-PE, suggesting that this ratio may serve as an important biomarker for assessing disease severity. The uric acid/creatinine ratio is a crucial parameter in evaluating glomerular filtration rate decline and renal perfusion impairment in preeclampsia patients [28]. In the literature, Piani et al. reported that the uric acid/creatinine ratio was significantly higher in women who developed preeclampsia in all trimesters of pregnancy. They found that pregnant women with high uric acid/creatinine ratios in the third trimester were more likely to develop preeclampsia (OR: 1.29) and showed a strong association with adverse neonatal outcomes (OR: 1.33) [28]. Our findings further support the clinical relevance of the uric acid/creatinine ratio in characterizing preeclampsia and informing prognosis. We observed that this ratio was significantly associated with disease severity and CANO in both EO-PE and LO-PE cases. However, for CAMO, a significant association was observed only in the EO-PE group.
The creatinine to body weight ratio is a valuable metric in predicting various health outcomes, including diabetes, muscle mass, mortality, and liver disease [29–31]. In the pathophysiology of preeclampsia, decreased renal perfusion, a reduced glomerular filtration rate, and increased systemic vascular resistance play a crucial role [4]. While creatinine levels serve as an indicator of renal function, their correlation with body weight provides a more precise assessment by accounting for individual variability. In our study, the creatinine/body weight ratio was not classified as a significant diagnostic marker for either EO-PE or LO-PE. Although it demonstrated notable predictive performance for CANO in the EO-PE group, it did not show a significant association with CAMO in either EO-PE or LO-PE groups, limiting its broader clinical utility. However, it was significantly higher in cases of severe preeclampsia. To our knowledge, creatinine/body weight ratio has been studied for the first time in preeclampsia cases.
AST/PLT ratio (APRI) is considered an important parameter reflecting hepatic dysfunction and coagulation system disorders associated with preeclampsia. Hepatic microvascular insufficiency, hepatocyte necrosis, and sinusoidal congestion due to preeclampsia contribute to elevated AST levels and platelet depletion [32]. Therefore, the AST/PLT ratio may serve as a marker for determining disease severity. In our study, the AST/PLT ratio demonstrated discriminative ability for distinguishing EO-PE and LO-PE from controls and was identified as a prognostic marker for severe preeclampsia. Similarly, it was significantly associated with CAMO in both EO-PE and LO-PE groups, while its association with CANO was limited to the EO-PE group. In the literature, Ozkan et al. reported that APRI levels were significantly higher in the severe preeclampsia group compared to mild preeclampsia, gestational hypertension, and control groups [33]. Ipek et al. observed higher first trimester APRI levels in the superimposed preeclampsia group compared to the chronic hypertension and control groups [34]. These findings emphasize the clinical importance of the AST/PLT ratio as a marker of liver dysfunction in preeclampsia and suggest its potential utility in risk stratification and disease management.
Previous studies have suggested that the AST/ALT ratio may serve as a potential marker for evaluating hepatic dysfunction associated with preeclampsia, particularly in cases complicated by HELLP syndrome. Kuzmin et al. reported that preeclampsia and HELLP syndrome may lead to hepatic sinusoidal obstruction due to fibrin deposition, causing ischemic damage and hepatocyte necrosis through a sinusoidal obstruction syndrome (SOS)-like mechanism [7]. Similarly, Hassen et al. found that AST levels were significantly higher in preeclamptic women compared to normotensive pregnant women, suggesting that AST elevation may be an indicator of liver damage. ALT levels also increased, though the rise was less pronounced compared to AST [35]. In a study conducted by Chen et al., the relationship between the development of preeclampsia in the second pregnancy and the liver enzyme AST/ALT ratio was examined in women who had preeclampsia in the first pregnancy. According to the results of multivariate logistic regression analysis, the AST/ALT ratio was not significantly associated with the development of preeclampsia [36]. Similarly, in our study, the AST/ALT ratio did not demonstrate statistical significance in differentiating preeclampsia cases from controls, assessing disease severity, or in its association with CAMO or CANO. This discrepancy may be attributed to differences in study populations, subgroup classifications within preeclampsia, variations in methodology, or the heterogeneous nature of hepatic involvement in preeclampsia pathophysiology. Given that preeclampsia presents with a broad clinical spectrum, the degree of hepatic dysfunction may vary among affected patients. Therefore, further large-scale, prospective studies are needed to assess the prognostic value of the AST/ALT ratio and clarify its role in evaluating hepatic dysfunction in preeclampsia and related complications.
FIB-4 and FIB-5 are non-invasive indices used to assess liver fibrosis, primarily in patients with chronic liver diseases such as hepatitis B and C, and non-alcoholic fatty liver disease (NAFLD). These scores help in predicting liver-related outcomes and are increasingly being explored for other prognostic applications [9, 16, 37]. In preeclampsia, hepatic microvascular damage, endothelial dysfunction, and systemic inflammatory processes affect liver function, potentially leading to changes in FIB-4 and FIB-5 values. In our study, we evaluated the associations between these indices and the presence of preeclampsia, as well as their relationships with key clinical outcomes. FIB-4 was significantly elevated in both EO-PE and LO-PE groups compared to controls, while FIB-5 was higher only in EO-PE cases. In terms of CANO, both FIB-4 and FIB-5 were significantly associated with CANO in EO-PE cases, but not in LO-PE. FIB-4 was significantly associated with CAMO in both EO-PE and LO-PE groups, whereas FIB-5 did not demonstrate a significant association in either group. Furthermore, both indices were significantly elevated in severe versus mild preeclampsia, supporting their potential utility as markers of disease severity. A previous study by Ozer et al. found that FIB-4 increased with the severity of preeclampsia but did not significantly correlate with CANO [38]. To our knowledge, FIB-5 has not been previously investigated in preeclampsia cases, making our study one of the first to explore its potential relevance.
Our study has several limitations. First, due to its retrospective design, the dynamic changes of biomarkers over the course of pregnancy could not be fully monitored, and patient data were evaluated retrospectively. Second, the study was conducted at a single center, which may limit the generalizability of the findings to broader populations. Validation in multicenter studies with larger, more diverse cohorts is essential to ensure the reproducibility of these results. Third, we could not evaluate the utility of these biomarkers earlier in gestation, prior to the clinical onset of preeclampsia. Since all laboratory data were collected at the time of diagnosis, the potential of these indices as early screening or risk stratification tools remains unknown. Future prospective studies with serial biomarker assessments in early pregnancy are essential to determine their predictive value before symptom onset. Fourth, potential confounding variables, such as comorbid conditions, treatment protocols, and individual variations in biochemical responses, were not fully accounted for, which may have influenced the findings. Fifth, the use of a CAMO and CANO, which combines a range of perinatal complications of varying severity, may dilute the specific predictive power of individual indices. Future studies should consider outcome-specific modeling or weighted composite scoring to enhance clinical interpretability. Considering these limitations, more comprehensive, prospective, and multicenter studies are warranted to validate the clinical value of these biomarkers in the early detection, risk stratification, and management of preeclampsia.
Conclusions
This study demonstrates that several inflammatory and metabolic indices, particularly the uric acid/albumin ratio and fibrinogen/uric acid ratio, are strongly associated with EO-PE and LO-PE, the presence of CAMO, CANO, and disease severity. The high AUC values observed for these parameters highlight their strong diagnostic and prognostic utility. Conversely, the AST/ALT ratio was not significantly associated with preeclampsia diagnosis, disease severity, differentiation of CAMO or CANO. Further prospective and multicenter studies are needed to validate these findings and establish standardized clinical applications for these indices in preeclampsia management.
Acknowledgements
Not applicable.
Author contributions
Design: RDPlanning: RD, BB, AAFData Acquisition: RD, BB, AAF, MAO, GK, ZSData analysis: RD, BB, AAF, DDBManuscript writing: RD, BB, AAF, MAO, GK, ZS, DOA, ZVYFinal Approval: RD, BB, AAF, MAO, GK, ZS, DOA, ZVY.
Funding
The authors received no financial support for this article’s research, authorship, and publication.
Data availability
The dataset analyzed during the current study is available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
This study was conducted in accordance with the Declaration of Helsinki, and ethical approval was obtained from the Ankara Etlik City Hospital Ethics Committee (approval number: AESH-BADEK–2025-036). In this study, due to its retrospective nature, informed consent was waived with the approval of the Ethics Committee of Ankara Etlik City Hospital.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Clinical trial number
Not applicable.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Ruken Dayanan, Email: rukendayanan@gmail.com.
Burak Bayraktar, Email: drburakbayraktar@gmail.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The dataset analyzed during the current study is available from the corresponding author upon reasonable request.