Preeclampsia is a hypertensive disorder unique to pregnancy, typically occurring after 20 weeks of gestation. It is characterized by new-onset hypertension, proteinuria, and/or multi-organ dysfunction due to widespread endothelial injury and vasospasm. Despite being extensively studied for decades, its exact etiology remains incompletely understood, and it continues to pose a significant challenge in obstetrics. Globally, preeclampsia contributes to substantial maternal and perinatal morbidity and mortality, second only to postpartum hemorrhage in developing nations such as India.[1] The incidence of preeclampsia ranges between 5–9% worldwide, but higher rates are reported in low- and middle-income countries, where the burden of maternal morbidity is disproportionately greater. According to India’s National Eclampsia Registry, hypertensive disorders in pregnancy contribute to approximately 10.08% of maternal morbidity, with an estimated 50,000–60,000 maternal deaths annually worldwide attributed to preeclampsia and related complications. In addition, nearly half a million stillbirths and neonatal deaths are linked to this disorder each year. For every maternal death due to preeclampsia, 50–100 women suffer severe morbidity, underscoring the critical importance of early detection.[2] Long-term consequences extend beyond pregnancy, as women with preeclampsia are at a three-fold increased risk of developing chronic hypertension, two-fold higher risk of coronary artery disease, and nearly double the risk of stroke later in life. Therefore, early identification is vital not only for preventing immediate maternal-fetal complications but also for reducing long-term cardiovascular risk.[3] Preeclampsia is multifactorial in origin, with maternal, fetal, immunological, and placental contributors. Placental dysfunction is central to its development. Normally, trophoblastic invasion of spiral arteries leads to remodeling of uteroplacental circulation into low-resistance, high-capacitance vessels. In preeclampsia, this remodeling is defective, leading to high-resistance flow, hypoperfusion, and ischemia. This triggers the release of antiangiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), which antagonize vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), leading to systemic endothelial dysfunction.[4] Certain risk factors predispose women to preeclampsia, including primigravidity, multiple gestation, advanced maternal age (≥35 years), obesity, chronic hypertension, diabetes mellitus, renal disease, and autoimmune disorders such as antiphospholipid syndrome. Family history, low socioeconomic status, vitamin D deficiency, and long inter-pregnancy intervals further increase susceptibility.[5] Aim To evaluate the predictive role of uterine artery Doppler, serum PAPP-A, β-hCG, and mean arterial pressure in early detection of preeclampsia. Objectives 1. To assess the predictive accuracy of uterine artery Doppler, serum PAPP-A, β-hCG, and mean arterial pressure in identifying women at risk of preeclampsia. 2. To determine cutoff values of these markers for predicting early and late-onset preeclampsia in the study population. 3. To evaluate whether early initiation of preventive strategies (e.g., low-dose aspirin) in high-risk women can reduce disease progression.

The study population comprised all pregnant women attending the antenatal clinic at hospital. A prospective observational study was conducted. Sample Size A total of 400 antenatal women were included. Sample size was calculated using the formula: n=((1.96)^2×(S_n )(1-S_n ))/(L^2 P) Where Sn = anticipated sensitivity (0.90), L = absolute precision (0.1), and P = incidence of preeclampsia. After accounting for loss to follow-up, a sample size of 400 was finalized. Inclusion Criteria Pregnant women attending the antenatal clinic in the first trimester (≤14 weeks gestation). Exclusion Criteria Women presenting after 14 weeks of gestation. Women with chronic hypertension, renal disease, or multiple pregnancy. Procedure and Methodology At recruitment, detailed history, systemic and obstetric examination, and risk assessment were performed. Mean Arterial Pressure (MAP): Recorded with a mercury/aneroid sphygmomanometer, ensuring appropriate cuff size and proper technique. MAP was calculated as: MAP=(SBP+2(DBP))/3 MAP >86.5 mmHg (from ROC curve analysis) was considered predictive. Biochemical Markers (11–13+6 weeks): Blood samples were collected for serum PAPP-A and β-hCG, converted into multiples of median (MoM) adjusted for gestational age, ethnicity, maternal weight, and other variables. Thresholds: PAPP-A <1.08 MoM (cutoff from ROC curve). β-hCG <1.97 MoM (cutoff from ROC curve). Uterine Artery Doppler: Performed at 11–13+6 weeks and repeated at 18–20 weeks. Measurements were taken with a 3.5–5 MHz curvilinear transducer, insonation angle <30°, and calculation of mean pulsatility index (PI). A PI >95th percentile or persistent early diastolic notch was considered abnormal. Preventive Intervention: High-risk women were started on low-dose aspirin (75 mg daily) before 16 weeks. Follow-up: Women were followed throughout pregnancy for development of preeclampsia, maternal complications, delivery details, and neonatal outcomes. Sample Processing Serum PAPP-A and β-hCG were processed by accredited commercial laboratories using immunoassay-based techniques. Values were standardized as MoM. Statistical Methods Data were analyzed using SPSS version 21.0. Continuous variables: Mean ± SD, analyzed using independent t-test or Mann–Whitney U test. Categorical variables: Frequency/percentage, analyzed using Chi-square or Fisher’s exact test. Diagnostic accuracy of predictors: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV). ROC curve analysis determined optimal cutoff values for MAP, uterine artery PI, PAPP-A, and β-hCG. A p-value <0.05 was considered statistically significant. Data Collection Clinical data, ultrasound findings, laboratory results, and follow-up outcomes were systematically recorded in a structured proforma and entered into a computerized database for analysis.

Table 1: Baseline markers by outcome (n or Mean ± SD) and association with preeclampsia (PE) Marker (trimester) PE (n=28) No PE (n=372) Difference (PE − No PE) 95% CI (difference) Test p-value Mean arterial pressure (1st) mmHg 87.9 ± 4.04 84.22 ± 5.28 +3.68 +2.09 to +5.27 t-test <0.001 Uterine artery PI (1st) 1.94 ± 0.34 1.44 ± 0.25 +0.50 +0.37 to +0.63 t-test <0.001 Uterine artery PI (2nd) 1.51 ± 0.19 1.18 ± 0.26 +0.33 +0.26 to +0.41 t-test <0.001 Serum PAPP-A (MoM) 1.01 ± 0.29 1.59 ± 0.50 −0.58 −0.70 to −0.46 t-test <0.001 Serum β-hCG (MoM) 1.66 ± 0.56 2.58 ± 0.92 −0.92 −1.15 to −0.69 t-test <0.001 Incidence of PE in the cohort: 28/400 (7.0%). Table 1, Baseline comparison of clinical and biochemical markers between women who developed preeclampsia (PE, n=28) and those who remained normotensive (n=372) demonstrated significant differences across all parameters. Mean arterial pressure (MAP) in the first trimester was higher in the PE group (87.9 ± 4.04 mmHg) compared to controls (84.22 ± 5.28 mmHg), with a mean difference of +3.68 mmHg (95% CI: +2.09 to +5.27, p<0.001). Similarly, uterine artery pulsatility index (PI) was significantly elevated in both the first (1.94 ± 0.34 vs. 1.44 ± 0.25, difference +0.50, 95% CI: +0.37 to +0.63, p<0.001) and second trimesters (1.51 ± 0.19 vs. 1.18 ± 0.26, difference +0.33, 95% CI: +0.26 to +0.41, p<0.001). In contrast, biochemical markers showed a reduction in cases destined to develop PE. Serum PAPP-A was lower in the PE group (1.01 ± 0.29 MoM vs. 1.59 ± 0.50 MoM, difference −0.58, 95% CI: −0.70 to −0.46, p<0.001), and β-hCG values were also significantly reduced (1.66 ± 0.56 MoM vs. 2.58 ± 0.92 MoM, difference −0.92, 95% CI: −1.15 to −0.69, p<0.001). Table 2: Predictive accuracy of individual markers for any PE (n = 400) Marker (cut-off) TP FP FN TN Sensitivity % (95% CI) Specificity % (95% CI) PPV % NPV % AUC (95% CI) p (ROC) MAP > 86.5 mmHg 18 91 10 281 64.3 (44.1–80.7) 72.3 (67.5–76.6) 16.5 96.6 0.72 (0.62–0.80) <0.001 PI (1st) > 1.745 24 41 4 331 85.7 (67.3–95.9) 89.0 (85.3–91.9) 36.9 98.8 0.941 (0.90–0.97) <0.001 PI (2nd) > 1.265 20 108 8 264 71.4 (51.3–86.8) 71.0 (66.1–75.5) 15.6 97.1 0.836 (0.76–0.91) <0.001 PAPP-A < 1.085 MoM 23 60 5 312 83.9 (65.5–94.5) 82.1 (77.9–85.8) 27.7 98.4 0.902 (0.85–0.95) <0.001 β-hCG < 1.975 MoM 18 124 10 248 66.7 (46.7–83.1) 64.3 (59.3–69.0) 12.7 96.1 0.780 (0.71–0.84) <0.001 In table 3, Assessment of predictive accuracy for each marker revealed varied diagnostic performance. MAP > 86.5 mmHg yielded moderate sensitivity (64.3%, 95% CI: 44.1–80.7) and specificity (72.3%, 95% CI: 67.5–76.6), with an AUC of 0.72, reflecting modest discriminatory ability. First-trimester uterine artery PI > 1.745 demonstrated the best overall performance, with sensitivity 85.7% (95% CI: 67.3–95.9), specificity 89.0% (95% CI: 85.3–91.9), a positive predictive value (PPV) of 36.9%, and a negative predictive value (NPV) of 98.8%, with an AUC of 0.941 (p<0.001). Second-trimester PI > 1.265 also performed well, showing sensitivity 71.4% and specificity 71.0%, AUC 0.836. Biochemical markers demonstrated moderate to strong predictive ability. PAPP-A < 1.085 MoM identified 83.9% of PE cases with specificity of 82.1% and an AUC of 0.902, while β-hCG < 1.975 MoM had lower sensitivity (66.7%) and specificity (64.3%), with an AUC of 0.780. Table 3: Final cut-off values in this cohort (Youden/ROC) for predicting PE; stratified early vs late-onset remark Marker Final cut-off (this study) AUC (95% CI) MAP (1st) > 86.5 mmHg 0.72 (0.62–0.80) Uterine artery PI (1st) > 1.745 0.941 (0.90–0.97) Uterine artery PI (2nd) > 1.265 0.836 (0.76–0.91) PAPP-A (MoM) < 1.085 0.902 (0.85–0.95) β-hCG (MoM) < 1.975 0.780 (0.71–0.84) For table 3, Receiver operating characteristic (ROC) curve analysis determined the optimal cut-off values for each parameter in this population. MAP > 86.5 mmHg was retained as the best threshold, albeit with modest accuracy (AUC 0.72). For uterine artery Doppler, the first-trimester PI > 1.745 achieved excellent discrimination (AUC 0.941), while the second-trimester PI > 1.265 was also significant (AUC 0.836). Biochemical cut-offs were identified as PAPP-A < 1.085 MoM (AUC 0.902) and β-hCG < 1.975 MoM (AUC 0.780). These findings highlight the superior performance of Doppler PI in the first trimester and PAPP-A as biochemical marker, particularly for early-onset disease. Table 4: Effect of early preventive strategy (low-dose aspirin) among screened high-risk women who developed PE Group (among those with PE) Early-onset PE Late-onset PE Early proportion % (95% CI) Aspirin given (n=18) 3 15 16.7% (6.0–39.7) Aspirin not given (n=10) 4 6 40.0% (17.7–68.2) Evaluation of preventive intervention IN TABLE 4, with low-dose aspirin in high-risk women demonstrated a shift in disease presentation. Among those given aspirin (n=18 with PE), only 16.7% developed early-onset PE, compared to 40.0% in the group that did not receive aspirin (n=10 with PE). Although this reduction in early-onset disease did not reach statistical significance due to small sample size (difference −23.3%, 95% CI: −54.0 to +9.0, p=0.21), the trend indicates that aspirin prophylaxis may delay the onset of preeclampsia, converting potentially severe early cases into later-onset, less morbid disease.

Baseline differences (Table 1). Cohort shows a clear first-trimester risk phenotype in those who later developed preeclampsia (PE): higher mean arterial pressure (MAP) and uterine artery pulsatility indices (UtA-PI) in both first and second trimesters, alongside lower first-trimester PAPP-A and β-hCG (all p<0.001). This pattern matches the placental-dysfunction model reported across large screening programs: UtA-PI and MAP capture the hemodynamic/placentation component, while depressed placenta-derived analytes (e.g., PAPP-A) reflect impaired trophoblast function. Large prospective and meta-analytic datasets have consistently shown that elevated UtA-PI in early pregnancy is associated with subsequent PE, with stronger associations for preterm/early-onset disease than for term disease. first-trimester UtA-PI separation (mean difference +0.50) is directionally concordant with these reports and of comparable or greater magnitude than pooled effects reported by Fang M et al.(2025)[6] and earlier second-trimester Doppler cohorts Sheetal Y et al.(2025)[7]. PAPP-A in PE group (mean ~1.0 MoM) is substantially lower than in unaffected pregnancies (mean ~1.6 MoM), mirroring first-trimester combined-screening studies in which PAPP-A adds independent information to maternal factors, MAP and UtA-PI. Contemporary evaluations suggest PlGF outperforms PAPP-A, but PAPP-A remains a useful component when PlGF is unavailable; between-group difference is coherent with that literature. Tzanaki I et al.(2025)[8] Predictive accuracy (Table 2). Among single markers, best discriminator is first-trimester UtA-PI >1.745 (AUC 0.94; Se 85.7%; Sp 89.0%), which is at the high end of what meta-analyses report when Doppler is measured to protocol and applied to a mixed-risk population, particularly for identifying cases that declare earlier in gestation. Pooled estimates for abnormal waveform/PI in the first trimester typically show high specificity (~92%) with modest sensitivity for early-onset PE (~48%); sensitivity is higher, plausibly reflecting (i) a cohort with stronger placental phenotype among eventual PE, and (ii) a quantitative PI cut-point rather than a simple “notch/abnormal” definition. Second-trimester PI performance in data (AUC 0.84) also aligns with earlier work indicating better identification of preterm than term PE at 22–24 weeks. Nikita KP et al.(2024)[9] PAPP-A <1.085 MoM in cohort shows strong discrimination (AUC 0.90; Se 83.9%; Sp 82.1%). While modern algorithms often prefer PlGF to PAPP-A for first-trimester screening, studies that directly compared the two still recognized PAPP-A as a reasonable alternative when PlGF is not accessible. β-hCG cut-off delivers only moderate accuracy (AUC 0.78), consistent with the literature where β-hCG contributes less than MAP/UtA-PI/PlGF and is usually not retained in the highest-performing models. Chen Y et al.(2024)[10] MAP >86.5 mmHg (AUC 0.72) provides modest stand-alone discrimination, which mirrors large multicenter experiences: MAP is a solid predictor but gains most of its value when combined with UtA-PI and biochemical markers in a Bayesian framework. negative predictive values (≥96% for all tests) echo the clinical utility of these screens to rule out near-term risk in low-risk individuals. Cut-offs (Table 3). ROC-optimized thresholds—UtA-PI(1st) >1.745, UtA-PI(2nd) >1.265, MAP >86.5 mmHg, PAPP-A <1.085 MoM—are consistent in direction with large studies that standardized MAP and UtA-PI measurements and converted serum markers to MoM. Even though dataset did not permit stable, separate cut-points for early- vs late-onset PE, the literature indicates that first-trimester UtA-PI and angiogenic markers better detect preterm PE, whereas term PE (with a weaker placental signature) is less readily identified by these biomarkers. Pooh RK.(2024)[11] Preventive aspirin signal (Table 4). Within the PE cases, the early-onset proportion was numerically lower among those who received low-dose aspirin after being screened high-risk (16.7% vs 40.0%), although the difference was not statistically significant due to small numbers. The direction of effect agrees with the ASPRE randomized trial, in which high-risk patients (identified by a combined first-trimester algorithm including MAP and UtA-PI) received 150 mg nocturnal aspirin and experienced a significant reduction in preterm PE compared with placebo. Current guidance from USPSTF/ACOG recommends 81 mg daily for individuals at increased risk, started after 12 weeks’ gestation; observational signal is therefore biologically plausible and guideline-concordant, albeit underpowered to prove causality. Huang T et al.(2025)[12]

The present prospective observational study of 400 antenatal women demonstrated that first-trimester uterine artery Doppler indices, serum PAPP-A, β-hCG, and mean arterial pressure (MAP) are significant predictors of preeclampsia. Women who subsequently developed preeclampsia had higher MAP and uterine artery pulsatility index in both trimesters, along with lower PAPP-A and β-hCG values, compared with normotensive women. Among the studied parameters, first-trimester uterine artery Doppler pulsatility index showed the highest predictive accuracy, while PAPP-A contributed significantly as a biochemical marker. MAP provided moderate stand-alone predictive ability, but, in combination with Doppler and biochemical markers, it enhanced risk stratification. Early identification of high-risk women allowed timely initiation of preventive measures such as low-dose aspirin, which showed a trend toward reducing early-onset preeclampsia.

1. Beyazıt F, Pek E, Daş M, Duran MN, Çakır DÜ, Şen BN, Kiraz HA, Yılmaz DK, Çetin EÜ. First-trimester prediction of early-onset preeclampsia using PAPP-A and mean arterial pressure. Biomolecules and Biomedicine. 2025 Jul 23. 2. Lee JY, Lee KA, Park SY, Kim SJ, Shim SY, Kim YJ, Park MH. Maternal Uterine Artery Doppler and Serum Marker in the First Trimester as Predictive Markers for Small for Gestational Age Neonates and Preeclampsia: A Pilot Study. Diagnostics. 2025 Jan 20;15(2):233. 3. Belousova V, Ignatko I, Bogomazova I, Zarova E, Pesegova S, Samusevich A, Kardanova M, Skorobogatova O, Kuzmina T, Kireeva N, Maltseva A. Combined First-Trimester PAPP-A and Free β-hCG Levels for the Early Diagnosis of Placenta Accreta Spectrum and Placenta Previa: A Case-Control Study. International Journal of Molecular Sciences. 2025 Jun 27;26(13):6187. 4. Choudhury SS, Deka B, Bora M, Das N. Long-Term Predictors of Gestational Hypertension: Placental Growth Factor, Pregnancy-Associated Plasma Protein-A and Free Beta-Hcg Versus Mean Arterial Pressure and Uterine Artery Doppler Versus a Combination of Both: A Comparative Study. The Journal of Obstetrics and Gynecology of India. 2024 Apr;74(2):125-30. 5. Swiercz G, Zmelonek-Znamirowska A, Szwabowicz K, Armanska J, Detka K, Mlodawska M, Mlodawski J. Evaluating the predictive efficacy of first trimester biochemical markers (PAPP-A, fβ-hCG) in forecasting preterm delivery incidences. Scientific Reports. 2024 Jul 13;14(1):16206. 6. Fang M, Gao X. Feasibility of using a multivariate serum biomarker model in early pregnancy to predict gestational hypertension. Technology and Health Care. 2025 Mar;33(2):1046-55. 7. Sheetal Y, Baliga A, Dixit H, Tiwari R, Prashant MC, Syed AK. Prediction of preeclampsia and intrauterine growth restriction by second trimester serum B-HCG and uterine artery colour Doppler velocimetry in Primigravidas. Journal of Contemporary Clinical Practice. 2025 Mar 30;11:993-8. 8. Tzanaki I, Makrigiannakis A, Lymperopoulou C, Al-Jazrawi Z, Agouridis AP. Pregnancy-associated plasma protein A (PAPP-A) as a first trimester serum biomarker for preeclampsia screening: a systematic review and meta-analysis. The Journal of Maternal-Fetal & Neonatal Medicine. 2025 Dec 31;38(1):2448502. 9. Nikita KP, Gupta G. To study the role of serum biomarkers combined with uterine artery doppler in prediction of intrauterine growth retardation. Int J Acad Med Pharm. 2024;6(5):866-71. 10. Chen Y, Dai X, Hu T, Jiang C, Pan Y. Clinical value of prenatal screening markers in early pregnancy combined with perinatal characteristics to predict fetal growth restriction. Translational Pediatrics. 2024 Jul 29;13(7):1071. 11. Pooh RK. First‐trimester preterm preeclampsia prediction model for prevention with low‐dose aspirin. Journal of Obstetrics & Gynaecology Research. 2024 May 1;50(5). 12. Huang T, Rashid S, Wang YG, Woo RS, Priston M, Gibbons C, Bedford M, Mei-Dan E. Modified multiple marker aneuploidy screening as a primary screening test for preeclampsia: A validation study. Pregnancy Hypertension. 2025 Sep 1;41:101239.