Association between FAR, PAR, APRI and adverse neonatal outcomes in pregnancies complicated by intrahepatic cholestasis

Introduction

Intrahepatic cholestasis (IHCP) is the most common liver disease during pregnancy. It typically presents in the third trimester, characterized by itching and liver dysfunction, and tends to resolve spontaneously postpartum [1], [2], [3]. Although the exact etiology is not fully understood, it is believed to arise from the interaction of genetic, hormonal, and environmental factors [4]. Clinically, although the course is generally benign in the mother, elevated maternal bile acid levels may increase perinatal morbidity and mortality. It has been associated with serious neonatal complications such as preterm birth, meconium aspiration, fetal distress, and intrauterine death [5], [6], [7]. Total bile acids and transaminase levels may increase, particularly in severe cases, and are associated with poor perinatal outcomes; however, these parameters alone are insufficient to predict all risks [8], 9]. Therefore, the investigation of new, practical biomarkers that can predict poor neonatal outcomes in IHCP is clinically important.

Inflammatory indicators, including the fibrinogen/albumin ratio (FAR), platelet/albumin ratio (PAR), and AST/platelet ratio (APRI), offer critical insights for the diagnosis and prognosis of liver disorders [10]. Nonetheless, the function of these indicators, particularly in forecasting neonatal outcomes related to IHCP, remains ambiguous.

This study aimed to assess the correlation of FAR, PAR, and APRI ratios with laboratory parameters and perinatal/neonatal outcomes by comparing pregnant women diagnosed with intrahepatic cholestasis to healthy pregnant women; furthermore, we intended to analyze the predictive capacity of these markers for adverse neonatal prognosis.

Materials and methods

This retrospective comparison study involved an examination of the records of pregnant women who delivered at a tertiary obstetrics facility from January 2023 to January 2025. The study comprised 165 pregnant women diagnosed with intrahepatic cholestasis (IHCP) and 155 healthy pregnant women.

The IHCP group comprised subjects exhibiting prevalent pruritus throughout gestation, serum total bile acid concentrations ≥10 μmol/L, and/or heightened liver enzymes (notably AST/ALT) [1]. A perinatologist established the diagnosis based on clinical and analytical evidence. The control group comprised healthy pregnant women devoid of any history of systemic diseases, pregnancy problems, or fetal defects. The group was paired with the IHCP group via a one-to-one matching technique based on maternal age and gestational week. Both groups included cases of non-hepatic disorders, such as hypothyroidism and anemia; however, those with a documented history of liver diseases, including viral hepatitis, autoimmune hepatitis, cirrhosis, or cholelithiasis, were excluded from the study.

Demographic information (age, body mass index, gravidity, parity), clinical features, and laboratory values (fibrinogen, albumin, AST, platelet count) for all cases were acquired from the electronic hospital record system during the data collecting process. The subsequent ratios were derived from this data: The Fibrinogen/Albumin Ratio (FAR), Platelet/Albumin Ratio (PAR), and AST/Platelet Ratio Index (APRI) are defined as follows: APRI = ((AST/upper limit value (40 U/L))/platelet count (10⁹/L)] × 100. The assessed perinatal and neonatal outcomes were gestational age, birth weight, fetal growth restriction (FGR), Apgar scores, necessity for neonatal intensive care unit (NICU) admission, and respiratory problems. A composite unfavorable newborn outcome was characterized by the occurrence of at least one of the following conditions: 5 min Apgar score <7, respiratory distress syndrome (RDS), meconium aspiration syndrome, neonatal sepsis, or admission to the NICU.

This research has received approval from the Ethics Committee of Ankara Etlik City Hospital (approval no:AESH-BADEK-2025-0305, date: 30.04.2025) and was done in compliance with the principles of the Declaration of Helsinki.

Results

The study comprised 165 pregnant women diagnosed with intrahepatic cholestasis and 155 healthy pregnant women. No statistically significant variations were observed in the demographic characteristics of the two groups for maternal age, body mass index (BMI), gestational age, gravidity, and parity (p>0.05; Table 1). No significant differences were seen between the groups for the occurrence of comorbid conditions (p = 0.446).

Upon examination of laboratory data, fibrinogen levels (543 (298–841) mg/dL), AST levels (44 (9–352) U/L), FAR (15.8 (7.1–25.3)), and APRI (0.46 (0.06–5.71)) were significantly elevated compared to the healthy group (all p<0.05). Albumin concentrations were elevated in the healthy cohort (36.5 ± 3.1 g/dL; p<0.05). Despite elevated PAR levels in the cholestasis group, this disparity was marginally significant (p = 0.057; Table 1). The incidence of birth before 37 weeks was elevated in the cholestasis group; however, this disparity was not statistically significant (p = 0.057). The cholestasis group exhibited a considerably decreased median birth weight of 2,950 g (p<0.05). The composite unfavorable neonatal outcome rate was 20.6 % in the IHCP group and 11 % in the healthy group (p = 0.022; Table 2).

In a comparison between cases with poor prognosis (n = 51) and those with good prognosis (n = 269), FAR levels were significantly elevated in the bad prognosis group (median: 15 (9.5–24.12); p = 0.015; Table 3). No substantial differences were observed between the groups regarding PAR and APRI values (p>0.05). The ROC curve study for FAR indicated that its diagnostic accuracy in predicting adverse neonatal outcomes is constrained (AUC: 0.607; 95 % CI: 0.52–0.69; p = 0.015; Table 4, Figure 1). The ideal cutoff value for FAR was established at 14.7, yielding a sensitivity of 58 % and a specificity of 63 %.

Figure 1:

Receiver operating characteristics (ROC) curves of FAR value.

In the multivariate logistic regression analysis, none of the variables in the model (AST, APRI, fibrinogen, albumin) demonstrated statistical significance as independent predictors (all p>0.05), including FAR. The model’s explanatory power was determined to be constrained; no variable appeared as a significant independent predictor.

Discussion

This study examined the correlation between systemic inflammation markers, including the fibrinogen/albumin ratio (FAR), platelet/albumin ratio (PAR), and AST/platelet ratio (APRI), and perinatal and neonatal outcomes in pregnant women diagnosed with intrahepatic cholestasis. Our data indicate that FAR and APRI values were markedly elevated in the IHCP group relative to healthy pregnant women. Nonetheless, only the FAR value exhibited a substantial correlation with adverse neonatal outcomes; however, this correlation did not attain the status of an independent predictor in multivariate analyses.

Intrahepatic cholestasis often does not present a grave risk to the mother; rather, it is linked to considerable fetal morbidities, including preterm birth, respiratory distress, and intrauterine demise [11]. Elevated bile acid concentrations transmitted to the fetus through the placenta heighten the risk of fetal arrhythmia, preterm, and intrauterine demise [12], 13]. Elevated bile acid levels correlate with an increased risk of fetal problems, particularly at concentrations exceeding 40 μmol/L [14]. Measuring bile acid levels presents technical challenges and temporal variability, highlighting the need for the creation of more practical and reliable biomarkers.

Recent studies have shown that some hematological markers linked to systemic inflammation possess predictive significance in liver disorders [15], [16], [17]. Specifically, ratings like APRI and FIB-4 can be employed with moderate to high accuracy in identifying advanced fibrosis and cirrhosis [18], 19]. Literature indicates that APRI ratings assessed during both the first and third trimesters are highly correlated with the onset of IHCP and are markedly elevated in patient groups relative to control groups [20], [21], [22]. Furthermore, FAR has been demonstrated to be markedly increased in cases of severe preeclampsia [23]. The existing literature about the predictive significance of markers like FAR and PAR in pregnant cholestasis is scarce.

Our findings indicates that the markedly elevated levels of APRI and FAR in the IHCP group may signify liver damage. This discovery aligns with the current research about liver dysfunction in cholestasis [24]. In the ROC analysis, the predictive capability of FAR for adverse neonatal outcomes was determined to be constrained (AUC: 0.607). At the threshold value of 14.7 established by the Youden index, sensitivity was assessed at 58 %, while specificity was evaluated at 63 %. This outcome demonstrates that FAR alone is inadequate for forecasting unfavorable prognosis.

FAR values demonstrated a substantial correlation with adverse neonatal outcomes in univariate analysis. This connection lost its statistical significance when subjected to multivariate logistic regression analysis. This outcome indicates that the influence of FAR on adverse newborn results is inadequate in isolation and is eclipsed by other clinical variables. The AUC value of 0.607 found in the ROC analysis also reveals that FAR has limited ability to identify these outcomes. Consequently, whereas FAR seems to correlate with adverse newborn outcomes, its efficacy as an independent and reliable predictor in clinical practice is constrained. Ovadia and colleagues also observed that biochemical indicators possess restricted predictive significance in IHCP, necessitating a comprehensive examination for clinical decision-making [25].

In this study, despite elevated PAR levels in the IHCP group, they were not statistically significant. This outcome indicates that platelet and albumin levels may be affected by several physiological and environmental variables throughout pregnancy [26]. Thus, PAR may inadequately represent liver disease or worse newborn outcomes. The sparse literature regarding the predictive relevance of PAR in IHCP renders the clinical significance of this finding ambiguous. This work is significant as one of the limited investigations assessing the predictive use of readily obtainable biomarkers like FAR and APRI in IHCP. Nonetheless, additional research including bigger cohorts and performed in a multicenter context is required to ascertain the influence of these markers on clinical decision-making.

This study’s strengths encompass the utilization of a control group matched by age and gestational week, as well as a thorough assessment of biomarkers by ROC and regression analysis. The retrospective design and single-center character of the study may restrict the generalizability of the findings.

Conclusions

The FAR and APRI values were markedly elevated in the intrahepatic cholestasis cohort. The predictive capacity of these indicators for adverse neonatal outcomes remains constrained. These ratios may serve as auxiliary factors in clinical assessments; nevertheless, they should not be utilized in isolation for decision-making. Our data indicate that the prognostic potential of these biomarkers necessitates additional examination.