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While imaging remains the cornerstone of prenatal diagnosis, limitations in sensitivity and availability necessitate the exploration of adjunctive biomarkers. Dysregulation of angiogenic pathways has been implicated in PAS pathogenesis. To evaluate maternal serum levels of angiogenic biomarkers—placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and soluble fms-like tyrosine kinase-1 (sFlt-1)—and to compare their expression between PAS and normal pregnancies. Methods This prospective case–control study was conducted at RSUP Dr. M. Djamil Padang between March and November 2025. Eighty-eight pregnant women were enrolled, comprising 44 PAS cases and 44 gestational age–matched controls with normal placentation. Maternal serum samples were collected at 32–34 weeks of gestation and analyzed for PlGF, VEGF, and sFlt-1 using enzyme-linked immunosorbent assay (ELISA). Demographic, obstetric, ultrasound, laboratory, and neonatal data were recorded. Statistical analysis was performed using appropriate parametric and non-parametric tests, with p &lt; 0.05 considered statistically significant. Results Maternal demographic characteristics, fetal biometric parameters, neonatal outcomes, and baseline biochemical profiles were comparable between groups. Median maternal serum PlGF and VEGF levels were significantly lower in the PAS group compared with controls (PlGF: 3.825.660 vs 4.086.680 pg/mL, p = 0.032; VEGF: 8.713.645 vs 12.524.675 pg/mL, p = 0.008). Although sFlt-1 levels showed a decreasing trend in PAS cases, the difference was not statistically significant (p = 0.102). Alpha-fetoprotein (AFP) levels did not differ significantly between groups (p = 0.114). Conclusion PAS is associated with significant reductions in maternal serum PlGF and VEGF, reflecting angiogenic dysregulation and abnormal placental invasion. These biomarkers may serve as complementary tools to imaging modalities for improving prenatal detection of PAS. Larger studies are warranted to validate their clinical utility and integration into diagnostic algorithms. \" } { \"@context\": \"http://schema.org\", \"@type\": \"BreadcrumbList\", \"itemListElement\": [ { \"@type\": \"ListItem\", \"position\": \"1\", \"item\": { \"@id\": \"https://f1000research.com/\", \"name\": \"Home\" } }, { \"@type\": \"ListItem\", \"position\": \"2\", \"item\": { \"@id\": \"https://f1000research.com/browse/articles\", \"name\": \"Browse\" } }, { \"@type\": \"ListItem\", \"position\": \"3\", \"item\": { \"@id\": \"https://f1000research.com/articles/15-213\", \"name\": \"Analysis of Maternal Serum PLGF, VEGF, and sFlt-1 in Placenta Accreta...\" } } ] } Home Browse Analysis of Maternal Serum PLGF, VEGF, and sFlt-1 in Placenta Accreta... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Yusrawati Y, Aladin A, Antonus PA et al. Analysis of Maternal Serum PLGF, VEGF, and sFlt-1 in Placenta Accreta Spectrum and Normal Pregnancy [version 1; peer review: awaiting peer review] . F1000Research 2026, 15 :213 ( https://doi.org/10.12688/f1000research.175924.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Analysis of Maternal Serum PLGF, VEGF, and sFlt-1 in Placenta Accreta Spectrum and Normal Pregnancy [version 1; peer review: awaiting peer review] Yusrawati Yusrawati https://orcid.org/0000-0002-4799-7202 1 , Aladin Aladin 1 , Puja Agung Antonus 1 , Muhammad Iqbal https://orcid.org/0009-0009-9743-5927 2 , Rahmalia Destri Hidayani 1 Yusrawati Yusrawati https://orcid.org/0000-0002-4799-7202 1 , Aladin Aladin 1 , [...] Puja Agung Antonus 1 , Muhammad Iqbal https://orcid.org/0009-0009-9743-5927 2 , Rahmalia Destri Hidayani 1 PUBLISHED 09 Feb 2026 Author details Author details 1 Obstetrics and Gynecology, Universitas Andalas Fakultas Kedokteran, Padang, West Sumatra, Indonesia 2 Anatomy, Universitas Andalas Fakultas Kedokteran, Padang, West Sumatra, Indonesia Yusrawati Yusrawati Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Aladin Aladin Roles: Conceptualization, Data Curation, Methodology Puja Agung Antonus Roles: Conceptualization, Data Curation, Methodology Muhammad Iqbal Roles: Conceptualization, Data Curation, Methodology Rahmalia Destri Hidayani Roles: Conceptualization, Data Curation, Methodology OPEN PEER REVIEW REVIEWER STATUS AWAITING PEER REVIEW This article is included in the Cell & Molecular Biology gateway. Abstract Background Placenta Accreta Spectrum (PAS) is a severe obstetric condition characterized by abnormal placental trophoblast invasion into the myometrium, leading to significant maternal morbidity and mortality. While imaging remains the cornerstone of prenatal diagnosis, limitations in sensitivity and availability necessitate the exploration of adjunctive biomarkers. Dysregulation of angiogenic pathways has been implicated in PAS pathogenesis. To evaluate maternal serum levels of angiogenic biomarkers—placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and soluble fms-like tyrosine kinase-1 (sFlt-1)—and to compare their expression between PAS and normal pregnancies. Methods This prospective case–control study was conducted at RSUP Dr. M. Djamil Padang between March and November 2025. Eighty-eight pregnant women were enrolled, comprising 44 PAS cases and 44 gestational age–matched controls with normal placentation. Maternal serum samples were collected at 32–34 weeks of gestation and analyzed for PlGF, VEGF, and sFlt-1 using enzyme-linked immunosorbent assay (ELISA). Demographic, obstetric, ultrasound, laboratory, and neonatal data were recorded. Statistical analysis was performed using appropriate parametric and non-parametric tests, with p < 0.05 considered statistically significant. Results Maternal demographic characteristics, fetal biometric parameters, neonatal outcomes, and baseline biochemical profiles were comparable between groups. Median maternal serum PlGF and VEGF levels were significantly lower in the PAS group compared with controls (PlGF: 3.825.660 vs 4.086.680 pg/mL, p = 0.032; VEGF: 8.713.645 vs 12.524.675 pg/mL, p = 0.008). Although sFlt-1 levels showed a decreasing trend in PAS cases, the difference was not statistically significant (p = 0.102). Alpha-fetoprotein (AFP) levels did not differ significantly between groups (p = 0.114). Conclusion PAS is associated with significant reductions in maternal serum PlGF and VEGF, reflecting angiogenic dysregulation and abnormal placental invasion. These biomarkers may serve as complementary tools to imaging modalities for improving prenatal detection of PAS. Larger studies are warranted to validate their clinical utility and integration into diagnostic algorithms. READ ALL READ LESS Keywords Placenta accreta spectrum; angiogenesis; PlGF; VEGF; sFlt-1; prenatal diagnosis. Corresponding Author(s) Yusrawati Yusrawati ( [email protected] ) Close Corresponding author: Yusrawati Yusrawati Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2026 Yusrawati Y et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Yusrawati Y, Aladin A, Antonus PA et al. Analysis of Maternal Serum PLGF, VEGF, and sFlt-1 in Placenta Accreta Spectrum and Normal Pregnancy [version 1; peer review: awaiting peer review] . F1000Research 2026, 15 :213 ( https://doi.org/10.12688/f1000research.175924.1 ) First published: 09 Feb 2026, 15 :213 ( https://doi.org/10.12688/f1000research.175924.1 ) Latest published: 09 Feb 2026, 15 :213 ( https://doi.org/10.12688/f1000research.175924.1 ) Introduction Placenta Accreta Spectrum (PAS) is a pathological pregnancy condition characterized by abnormal invasion of the placental trophoblast into the uterine myometrium, sometimes penetrating the serosa or surrounding organs. 1 , 2 The global incidence of PAS is increasing, largely associated with the rising rates of cesarean delivery and other uterine surgeries, which create decidual defects and elevate the risk of abnormal placental implantation. 3 , 4 Previous uterine surgery in women with PAS increases the likelihood of peripartum hysterectomy. 5 Beyond these risk factors, vitamin D deficiency is suspected to contribute to PAS by affecting endometrial decidualization and trophoblast invasion. 6 Women with PAS are at high risk for obstetric complications, including postpartum hemorrhage, pelvic organ injury, coagulopathy, and even maternal death. 7 Early diagnosis and optimal management planning are therefore crucial to reduce morbidity and mortality associated with PAS. 8 Currently, imaging—particularly ultrasonography and magnetic resonance imaging (MRI)—remains the primary diagnostic method for PAS. Transvaginal and transabdominal ultrasonography are frequently used to detect specific signs of PAS, while MRI serves as an additional tool for cases difficult to identify with ultrasonography. 1 , 2 However, both techniques have limitations, including equipment availability, operator expertise, and sensitivity in detecting early-stage PAS. 4 To improve early PAS detection, research has focused on identifying specific biomarkers for prenatal diagnosis. Key biomarkers showing potential include placental growth factor (PLGF), vascular endothelial growth factor (VEGF), and soluble fms-like tyrosine kinase-1 (sFLT-1), 7 which play important roles in angiogenesis and placental hypoxia, central mechanisms in PAS pathogenesis. 8 PLGF, a member of the VEGF family, is critical for regulating placental angiogenesis by promoting endothelial cell proliferation and differentiation, contributing to normal placental vascularization. 9 Studies show that maternal serum PLGF levels differ significantly between normal pregnancies and those complicated by PAS, with reduced levels in some PAS cases indicating impaired angiogenesis and abnormal trophoblast invasion. 10 VEGF is a key angiogenic factor that stimulates blood vessel formation and vascular permeability, inducing endothelial proliferation and enhancing adhesion molecule expression critical for vascular remodeling. 11 In PAS, excessive VEGF expression may contribute to uncontrolled trophoblast invasion into the myometrium, leading to abnormal placental implantation. 7 The imbalance between angiogenic factors (VEGF, PLGF) and antiangiogenic factors (sFLT-1) is pivotal in preeclampsia pathogenesis and can also reflect placental hypoxia in PAS compared with normal pregnancy. 12 , 13 Soluble fms-like tyrosine kinase-1 (sFLT-1), a natural VEGF antagonist, inhibits VEGF-receptor interaction, reducing angiogenesis. 1 Elevated sFLT-1 levels are associated with angiogenic imbalance and placental hypoxia, commonly seen in PAS patients. 2 Histopathological analysis is essential for understanding PAS mechanisms. Histologically, PAS is characterized by the absence of a normal basal decidua layer, allowing direct trophoblast invasion into the myometrium. 4 Studies report increased chronic inflammation, abnormal vascular changes, and fibrosis in areas of abnormal placental invasion. 10 Immunohistochemistry confirms abnormal expression of angiogenic and inflammatory markers such as MMP-1, EGF, and VEGF-A. 11 Recent research associates these biomarker expressions with the degree of placental invasion and PAS severity. 8 Therefore, this study aims to analyze the expression of angiogenic biomarkers PLGF, VEGF, and sFLT-1, as well as the histopathological characteristics of placental hypoxia in PAS patients compared with normal pregnancies. Materials and methods This prospective case–control study was conducted at RSUP Dr. M. Djamil Padang between March, 2025 and November, 2025 to investigate maternal serum biomarkers (PlGF, VEGF, and sFlt-1) in placenta accreta spectrum (PAS) compared with normal pregnancy. Study participants The study population consisted of pregnant women who delivered at RSUP Dr. M. Djamil Padang. A total of 88 participants were enrolled, including 44 women with PAS (case group) and 44 women with normal pregnancies (control group). Diagnosis of PAS was established according to the FIGO PAS system into placenta accreta, increta, and percreta based on intraoperative and histopathological finding. Inclusion criteria were singleton pregnancy and absence of preeclampsia or other hypertensive disorders. Exclusion criteria included multiple gestations, hypertensive disorders of pregnancy, pregestational or gestational diabetes mellitus, thyroid disorders, autoimmune disease, significant anemia (hemoglobin <8 g/dL), chronic liver or renal disease, and maternal conditions known to affect angiogenic or inflammatory biomarkers. Sampling method A consecutive sampling method was used. Cases were recruited consecutively as women with suspected PAS undergoing cesarean delivery, confirmed by intraoperative findings and histopathology. Controls were selected from women with uncomplicated singleton pregnancies delivering during the same study period and frequency-matched to cases by gestational age (±1 week) and mode of delivery to minimize confounding. Data collection All maternal blood samples were collected between 32–34 weeks of gestation to reduce physiological gestational age–related variability in angiogenic biomarkers. Serum was separated by centrifugation and stored at −80°C until analysis. Concentrations of VEGF, PlGF, and sFlt-1 were measured using ELISA kits according to the manufacturer’s instructions. Ultrasound markers of PAS including placental lacunae, loss of the clear zone, abnormal bladder–uterine interface, and uterovesical hypervascularity were recorded. Statistical analysis Statistical analyses were performed using SPSS software (version XX, IBM Corp., Armonk, NY, USA). Data distribution was tested with the Shapiro–Wilk test. Independent t-tests were applied for normally distributed variables, while the Mann–Whitney U test was used for non-parametric data. Chi-square or Fisher’s exact tests were employed for categorical variables. A p-value < 0.05 was considered statistically significant. Ethical consideration This research protocol was approved by the Ethics Committee of the Faculty of Medicine, Universitas Andalas (Approval No. 536/UN.16.2/KEP-FK/2025). All participants provided written informed consent before inclusion. Confidentiality and anonymity were maintained, and the study adhered to the principles of the Declaration of Helsinki. Results Table 1 shows the maternal characteristics in the case group (Acreta Placenta) and the control group (Normal Placenta). The analysis results indicate the demographic and clinical profiles that serve as a comparative basis for further analysis regarding the differences in biomarkers between mothers with acreta placenta and the control group. The distribution of maternal age between the two groups shows homogeneity, with a mean age of 30.77 ± 5.73 years in the Acreta Placenta group and 31.07 ± 5.88 years in the control group. Parity shows equal distribution with a mean of 1.36 ± 1.37 in the study group compared to 1.25 ± 1.06 in the control group. However, there is a noticeable difference in the history of abortion, which shows a higher tendency in the Acreta Placenta group (0.48 ± 0.73) compared to the control group (0.23 ± 0.52). The anthropometric profile represented through the body mass index shows homogeneity between the two groups (23.13 ± 3.33 kg/m 2 vs 22.63 ± 3.03 kg/m 2 ). Table 1. Demographic and obstetric characteristics. Variables Case (Placenta Accreta) n = 44 Control (Normal Placenta) n = 44 Mean ± SD Min-Max Mean ± SD Min-Max Age (Year) 30.77 ± 5.73 16–45 31.07 ± 5.88 22–44 Parity 1.36 ± 1.37 0–5 1.25 ± 1.06 0–5 Abortion 0.48 ± 0.73 0–3 0.23 ± 0.52 0–2 IMT (kg/m 2 ) 23.13 ± 3.33 17.78–36.33 22.63 ± 3.03 15.98–30.45 Table 2 shows the results of the ultrasound examination indicating the variation in fetal growth between the two groups. The main biometric parameters include biparietal diameter (9.36 ± 0.84 cm vs 9.33 ± 0.74 cm), head circumference (32.63 ± 3.88 cm vs 33.20 ± 4.20 cm), abdominal circumference (32.26 ± 1.11 cm vs 31.96 ± 2.67 cm), femur length (7.23 ± 0.39 cm vs 7.23 ± 0.65 cm), and humerus length (6.29 ± 0.36 cm vs 6.30 ± 0.67 cm) which indicate the equivalence of fetal development in the case and control groups. The fetal hemodynamic parameters Systolic/Diastolic Umbilical Artery Ratio (DUAR) and Amniotic Fluid Index (AFI) also showed no significant disparity between the groups. Table 2. Ultrasound measurement results. Variables Case (Placenta Accreta) n = 44 Control (Normal Placenta) n = 44 Mean ± SD Min–Max Mean ± SD Min–Max BPD (cm) 9.36 ± 0.84 7.27–13.49 9.33 ± 0.74 5.59–10.94 HC (cm) 32.63 ± 3.88 21.33–49.29 33.20 ± 4.20 10.65–40.26 AC (cm) 32.26 ± 1.11 29.69–34.67 31.96 ± 2.67 19.23–35.29 FL (cm) 7.23 ± 0.39 6.00–7.80 7.23 ± 0.65 4.58–7.90 HL (cm) 6.29 ± 0.36 5.37–7.65 6.30 ± 0.67 2.48–7.70 DUAR 11.76 ± 5.75 2.21–38.65 12.82 ± 9.85 0.10–69.10 AFI 2.40 ± 0.67 1.70–5.85 2.38 ± 0.40 1.48–3.44 Table 3 shows that the perinatal results indicate a homogeneous outcome for birth weight between the two groups (2990.14 ± 391.34 grams vs 2996.11 ± 531.77 grams). The birth length also shows equality with a value of 46.77 ± 2.37 cm in the study group and 47.18 ± 4.11 cm in the control group. Table 3. Characteristics of labor and neonatal. Variables Case (Placenta Accreta) n = 44 Control (Normal Placenta) n = 44 Mean ± SD Min–Max Mean ± SD Min–Max Birth weight (grams) 2990.14 ± 391.34 2200–3830 2996.11 ± 531.77 675–3700 Birth length (cm) 46.77 ± 2.37 40–51 47.18 ± 4.11 30–59 Table 4 shows that maternal hemodynamic parameters indicate a stable mean arterial pressure (MAP) between the two groups (91.89 ± 7.28 mmHg vs 92.68 ± 13.14 mmHg). Biochemical profiles including liver function (SGOT, SGPT), renal function (urea, creatinine), and hematological parameters (hemoglobin) showed values within normal limits in both groups. However, significant variability was observed in the number of leukocytes and platelets in the Placenta Accreta group, which may reflect a heterogeneous physiological response to this pathological condition. Table 4. Hemodynamic and blood biochemical parameters. Variables Case (Placenta Accreta) n = 44 Control (Normal Placenta) n = 44 Mean ± SD Min–Max Mean ± SD Min–Max MAP (mmHg) 91.89 ± 7.28 80–110 92.68 ± 13.14 66–132 SGOT (U/L) 21.93 ± 5.72 10–35 24.65 ± 6.11 13–50 SGPT (U/L) 19.71 ± 10.74 4–42 24.37 ± 8.99 6–42 Urea (mg/dL) 14.98 ± 5.34 7–41 14.67 ± 3.24 5–25 Creatinine (mg/dL) 0.66 ± 0.21 0.30–1.70 0.69 ± 0.15 0.40–0.96 Hb (g/dL) 11.41 ± 1.20 7.60–13.00 11.56 ± 0.98 9.80–14.30 Leukocytes (cells/μL) 13.332.28 ± 9.418.51 6.66–36.000 9.895.27 ± 2.108.74 5.160–14.130 Thrombocytes (cells/μL) 204.274.98 ± 133.076.72 177–539.000 231.848.18 ± 706.70.32 11.320–475.000 Table 5 shows significant differences in the expression of several angiogenesis biomarkers between the Placenta Accreta group and the normal pregnancy group. The analysis results indicate a characteristic pattern of angiogenesis dysregulation in the Placenta Accreta condition. For the biomarker sFlt-1, although it shows a lower median value in the Placenta Accreta group (191.310 pg/mL) compared to the normal group (258.015 pg/mL), it is not statistically significant (p = 0.102). For the biomarker AFP with a median value of 247.100 ng/mL in the study group compared to 256.350 ng/mL in the control group, it is also not statistically significant (p = 0.114). However, there is a significant decrease in two key angiogenesis biomarkers. The median value of PlGF in the Placenta Accreta group (3.825.660 pg/mL) is significantly lower than in the normal group (4.086.680 pg/mL) with p = 0.032. In the VEGF biomarker, the Placenta Accreta group showed a significantly lower median value (8.713.645 pg/mL) compared to the normal group (12.524.675 pg/mL) with p = 0.008. This indicates specific dysregulation in the angiogenesis pathway in Placenta Accreta, particularly in aspects mediated by PlGF and VEGF. The significant decrease in these two pro-angiogenic biomarkers indicates a disruption in the normal angiogenesis process that may contribute to the pathogenesis of Placenta Accreta. This selective dysregulation pattern highlights the complexity of angiogenesis regulation in placental pathology. Table 5. Comparative analysis of biomarkers. Biomarkers Case (Placenta Accreta) Median Control (Normal Placenta) Median p-value sFlt-1 (pg/mL) 191.310 258.015 0.102 PlGF (pg/mL) 3.825.660 4.086.680 0.032* VEGF (pg/mL) 8.713.645 12.524.675 0.008* AFP (ng/mL) 247.1 256.35 0.114 Discussion This study presents the profile of angiogenic biomarkers in Placenta Accreta Spectrum (PAS). The main findings showed a significant reduction in maternal serum levels of Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF) in the PAS group compared to controls (p = 0.008 and p = 0.032, respectively), whereas levels of soluble Fms-like tyrosine kinase-1 (sFlt-1) and alpha-fetoprotein (AFP) exhibited a decreasing trend that was not statistically significant. The underlying mechanism of abnormal placental invasion in PAS is associated with decidual abnormalities, characterized by reduced, absent, or defective decidualization, which allows extravillous trophoblasts to penetrate deeper into maternal tissue. Molecular analyses indicate the involvement of two vascular formation mechanisms: vasculogenesis, the formation of new vessels from hemangiogenic cells via hemangioblastic differentiation regulated by VEGF and VEGFR, and angiogenesis, the growth of new branches from pre-existing vessels, in which PlGF plays a critical role. 14 The results indicate that maternal circulating VEGF levels were significantly lower in the PAS group compared with controls. This finding aligns with several previous studies. Uyanıkoğlu et al . (2018) reported significantly lower preoperative VEGF levels in placenta percreta (39.18 ± 11.98 pg/mL) compared to controls (85.87 ± 18.05 pg/mL, p < 0.001). Similarly, Schwickert et al . (2021) found significantly lower VEGF levels in the Abnormally Invasive Placenta group (285 pg/mL) compared to controls (391 pg/mL). In contrast, Faraji et al. reported that VEGF was not consistently a PAS marker, 15 showing a non-significant difference (p = 0.055), highlighting variability across studies. 15 – 17 The low VEGF levels in PAS cases may be explained by a decreased number of multinucleated giant cells (MNGCs) in the basal decidua, which are critical VEGF secretors during implantation. With fewer MNGCs, systemic VEGF production declines, resulting in lower free VEGF in maternal blood. Furthermore, invasive extravillous trophoblasts (iEVTs) that penetrate the basal layer show dual expression of vimentin and cytokeratin, reflecting epithelial–mesenchymal transition (EMT) similar to cancer cell invasion. VEGF appears to be used locally to enhance EVT motility and invasion rather than released into maternal circulation. This is supported by strong VEGF staining in local placental tissue, particularly at invasion sites and vascular lacunae, despite low maternal serum levels. 16 , 18 Therefore, low maternal VEGF in PAS is not due to complete cessation of production but rather decreased MNGC sources and local utilization for abnormal trophoblast invasion. Although sFlt-1 levels in this study did not differ significantly, the consistent decreasing trend aligns with most literature reporting lower sFlt-1 in PAS patients. A meta-analysis by Alzoub et al . (2022) confirmed significantly lower sFlt-1 in PAS compared to non-PAS controls (SMD = –7.76; 95% CI = –10.42 to –5.10; p < 0.0001). 19 Cai et al. similarly reported lower sFlt-1 levels in PAS (2075.57–2735.71 μg/L) compared with controls (2866.41 ± 226.77 μg/L, p = 0.001). 20 Zhang et al. reported median sFlt-1 levels of 32.7 ng/mL in controls versus 12.8 ng/mL in PAS (p < 0.0001), and found sFlt-1 nearly three times lower in PAS than in non-PAS women. 14 Physiologically, sFlt-1 is a placenta-specific protein acting as a natural VEGF antagonist, irreversibly binding VEGF and suppressing its physiological function, thus exerting strong antiangiogenic activity. 20 Low sFlt-1 in PAS is thought to be a secondary response to endometrium-myometrium injury, contributing to disease progression by removing the “brake” on angiogenesis. When VEGF increases while sFlt-1 decreases, this imbalance creates a highly pro-angiogenic and pro-invasive environment, promoting abnormal placental vessel formation and excessive trophoblast invasion into the myometrium, exacerbating PAS. 20 Therefore, low sFlt-1 is not merely a marker but plays a causal role in PAS pathogenesis. Similarly, PlGF levels were lower in the PAS group in this study. Uyanıkoğlu et al. reported lower PlGF in PAS (39.94 pg/mL) versus controls (76.65 pg/mL), 16 while Zhang et al. found higher PlGF in PAS (108 pg/mL) than controls (33 pg/mL), reflecting inter-study variability. 14 The present study supports the trend of PlGF reduction in PAS, indicating impaired placental angiogenesis. PAS primarily arises from a combination of placental dysfunction and a stressed microenvironment at abnormal implantation sites. Placentas developing over scar tissue receive high-flow blood from radial or arcuate arteries, triggering local oxidative stress and mechanical shear stress in the intervillous space. This stress disrupts normal syncytiotrophoblast function, suppressing PlGF synthesis and systemic release. Additionally, PlGF may be redirected locally to support invasive angiogenesis or suppressed by hypoxia and stress, resulting in lower maternal serum levels. 7 Variability between studies may be influenced by invasion severity (accreta, increta, percreta), gestational age at sampling, and biomarker assay methods. In this study, AFP levels in the PAS group (24.7 ng/mL) did not differ significantly from controls (25.6 ng/mL, p = 0.114). Cai et al reported higher AFP in PAS (127.33–140.12 U/mL) than in controls (111.62 ± 14.25 U/mL). 20 While some studies associate elevated AFP with PAS, possibly due to abnormal implantation, maternal-fetal interface damage, or increased placental vascular permeability, other factors such as maternal race, BMI, chronic illness, conception method, infection, medications, or non-pregnancy conditions (e.g., liver tumors, AFP-related genetic disorders) can affect AFP levels, limiting its specificity as a standalone marker. 21 These findings indicate that AFP is not a sensitive or specific single biomarker for PAS detection. Overall, this study confirms that angiogenic biomarkers such as VEGF, sFlt-1, and PlGF play key roles in PAS pathogenesis, particularly through effects on placental angiogenesis and abnormal trophoblast invasion. In contrast, AFP did not differ significantly and is influenced by multiple maternal and non-pregnancy factors, precluding its use as a single sensitive or specific marker for PAS. These results underscore the need for a multifactorial approach, integrating biomarker analysis, clinical evaluation, and histopathological data for more accurate PAS detection. The study was limited by a small sample size due to strict inclusion criteria, resulting in a longer period to achieve the desired number of participants. Additionally, variability in medical record data required imputation for incomplete datasets to maintain analysis quality. Conclusion PAS is associated with lower levels of maternal serum PlGF and VEGF, as well as histopathological findings such as the absence or thinning of the decidua basalis, abnormal remodeling of spiral arteries, and excessive extravillous trophoblast invasion. These biomarkers have the potential to serve as additional diagnostic tools complementing imaging for the early detection of PAS. Ethics approval and consent to participate The ethical implications of this study followed the provisions of the Declaration of Helsinki and were approved by the ethical committee of Universitas Andalas (Approval No. 536/UN.16.2/KEP-FK/2025). The participants approved and signed the informed consent. Participants hold the right to decline participation if they choose not to consent. The researcher assumes responsibility for covering all research-related expenses and associated costs. Consent for publication Not applicable. Availability of data and materials Figshare: Analysis of Maternal Serum PLGF, VEGF, and sFlt-1 in Placenta Accreta Spectrum and Normal Pregnancy. https://doi.org/10.6084/m9.figshare.31081786 . 22 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0) . References 1. 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Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 09 Feb 2026 ADD YOUR COMMENT Comment Author details Author details 1 Obstetrics and Gynecology, Universitas Andalas Fakultas Kedokteran, Padang, West Sumatra, Indonesia 2 Anatomy, Universitas Andalas Fakultas Kedokteran, Padang, West Sumatra, Indonesia Yusrawati Yusrawati Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Aladin Aladin Roles: Conceptualization, Data Curation, Methodology Puja Agung Antonus Roles: Conceptualization, Data Curation, Methodology Muhammad Iqbal Roles: Conceptualization, Data Curation, Methodology Rahmalia Destri Hidayani Roles: Conceptualization, Data Curation, Methodology Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 09 Feb 2026, 15:213 https://doi.org/10.12688/f1000research.175924.1 Copyright © 2026 Yusrawati Y et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Yusrawati Y, Aladin A, Antonus PA et al. Analysis of Maternal Serum PLGF, VEGF, and sFlt-1 in Placenta Accreta Spectrum and Normal Pregnancy [version 1; peer review: awaiting peer review] . 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