Preeclampsia complicates 28% of pregnancies globally and is responsible for approximately 76,000 maternal deaths and 500,000 perinatal deaths each year, the majority occurring in low and middleincome countries [1]. In India, the incidence of hypertensive disorders of pregnancy is reported to be 710%, with preeclampsia accounting for a significant proportion of intensive care admissions and preterm births [2,3]. The disorder is characterised by newonset hypertension and proteinuria or evidence of maternal organ dysfunction after 20 weeks of gestation, reflecting a systemic inflammatory response to defective placentation [4]. Despite advances in understanding its pathophysiology, the ability to predict preeclampsia before clinical onset remains limited, and aspirin prophylaxis initiated before 16 weeks has been shown to reduce the risk of preterm preeclampsia by over 60% in highrisk women [5,6]. Therefore, accurate firsttrimester identification of atrisk pregnancies is a public health priority. The underlying placental insult in preeclampsia is thought to be inadequate trophoblastic invasion of the spiral arteries, leading to highresistance uteroplacental circulation [7]. This pathological process can be detected noninvasively by uterine artery Doppler velocimetry. Increased impedance, evidenced by elevated pulsatility index (PI), resistance index (RI), and persistence of an early diastolic notch, has been consistently associated with subsequent development of preeclampsia, especially the earlyonset and severe forms [8,9]. A large body of evidence from European and Asian populations has demonstrated that uterine artery Doppler at 11–13⁺⁶ weeks, when combined with maternal factors, can detect approximately 4070% of preeclampsia cases at a 10% falsepositive rate [10,11]. However, the performance of these markers varies by ethnicity, parity, and body mass index, and few studies have been conducted exclusively in Indian settings [12]. Pregnancyassociated plasma proteinA (PAPPA), a glycoprotein produced by the syncytiotrophoblast, is already measured as part of the firsttrimester combined screening for aneuploidy. Low maternal serum levels of PAPPA in the first trimester have been linked to adverse pregnancy outcomes including preeclampsia, intrauterine growth restriction, and preterm birth [13,14]. PAPPA is believed to facilitate placental development by cleaving insulinlike growth factorbinding proteins, thereby increasing local bioavailability of insulinlike growth factors [15]. Reduced PAPPA may reflect impaired placentation, making it a biologically plausible marker for preeclampsia. Several metaanalyses have confirmed that low PAPPA (<0.4–0.5 MoM) is associated with a 2 to 4fold increased risk of preeclampsia [16,17]. The advantage of PAPPA lies in its routine availability; however, when used as a standalone test, its sensitivity is modest, and combination with biophysical markers such as uterine artery Doppler substantially improves predictive accuracy [18,19]. In the Indian clinical context, most firsttrimester screening protocols focus solely on aneuploidy. Incorporating preeclampsia prediction into the same visit using existing biochemical markers and a single Doppler examination could dramatically expand the benefit of early antenatal care without requiring additional expensive resources. Nevertheless, the utility of such an approach needs local validation, given the differences in baseline risk, body habitus, and genetic background of Indian women. The present study was designed to fill this gap by assessing the predictive performance of uterine artery Doppler indices and PAPPA in a small cohort of pregnant women attending a tertiary care hospital in Pune, India. The study aimed to determine whether these markers, alone or in combination, can serve as effective firsttrimester predictors of preeclampsia, thereby guiding prophylactic interventions and timely referral. OBJECTIVE The primary objective of this study was to evaluate the predictive ability of firsttrimester uterine artery Doppler indices (mean PI, RI, and presence of diastolic notching) and maternal serum PAPPA (MoM) for the development of preeclampsia in a cohort of Indian pregnant women. The study sought to quantify the sensitivity, specificity, positive predictive value, and negative predictive value of each marker individually and in combination, and to construct receiver operating characteristic (ROC) curves to establish optimum cutoff values for the local population. The secondary objective was to determine whether the combination of uterine artery Doppler and PAPPA improves the prediction of preeclampsia compared with either marker alone, and to assess the feasibility of integrating this dualmarker screen into the existing firsttrimester aneuploidy screening programme. By analysing a small but wellcharacterised sample, the study also aimed to generate preliminary data to inform larger multicentre studies and to explore the potential of a costeffective, singlevisit screening strategy that could be offered even in resourcelimited Indian settings.

Study Design and Participants This was a prospective observational cohort study conducted in the Department of Obstetrics and Gynaecology at a tertiary care teaching hospital in Pune, India, from 1 April 2025 to 25 January 2026. Women with a viable singleton pregnancy presenting for routine firsttrimester combined screening between 11 and 13⁺⁶ weeks of gestation were approached for participation. Gestational age was confirmed by crownrump length measurement. After obtaining written informed consent, 24 consecutive eligible women were enrolled. The study protocol was approved by the Institutional Ethics Committee (Ref. No: IEC/2025/OBG/15) and was carried out in accordance with the Declaration of Helsinki. Inclusion criteria: Women aged 18–40 years with a live singleton pregnancy at 11–13⁺⁶ weeks, who consented to provide blood samples for PAPPA estimation and to undergo transabdominal uterine artery Doppler examination, and who planned to deliver at the study hospital, were included. Exclusion criteria: Multiple gestations, pregnancies with major fetal structural or chromosomal anomalies, maternal history of chronic hypertension, preexisting renal disease, diabetes mellitus, autoimmune disorders, use of aspirin or anticoagulants before 16 weeks, and loss to followup before delivery were excluded. Women with miscarriage before 20 weeks or termination of pregnancy were also excluded. Data Collection Procedure At enrolment, demographic details (maternal age, parity, body mass index [BMI], and obstetric history) were recorded. All women underwent a standardised ultrasound examination using a Voluson E10 machine (GE Healthcare, USA) equipped with a 4–8 MHz transabdominal probe. Uterine artery Doppler velocimetry was performed according to the Fetal Medicine Foundation (FMF) protocol: a midsagittal section of the uterus was obtained, the cervical canal was identified, and colour Doppler was applied to locate the uterine artery as it crossed the external iliac vessels. Pulsedwave Doppler was then used to obtain three consecutive waveforms with good quality, and the PI and RI were measured on both sides. The mean PI and mean RI of the left and right arteries were calculated. The presence of an early diastolic notch (unilateral or bilateral) was noted. All Doppler examinations were performed by a single operator accredited by the FMF to minimise interobserver variability. On the same day, 5 mL of maternal venous blood was collected into a serum separator tube. Serum PAPPA was measured using the DELFIA® Xpress immunofluorescent platform (PerkinElmer, Finland) as part of the routine combined screening. Concentrations were converted to multiples of the median (MoM) adjusted for gestational age, maternal weight, ethnicity, and smoking status using the Prisca software. Women with PAPPA ≤0.5 MoM were classified as having low PAPPA. All participants received standard antenatal care according to institutional protocol. None received aspirin prophylaxis during the current pregnancy as the screening for preeclampsia risk was exploratory and not used to alter management. Participants were followed prospectively through pregnancy and delivery. The primary outcome was the development of preeclampsia, defined by the International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria: systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg on two occasions at least four hours apart after 20 weeks of gestation, accompanied by proteinuria (≥300 mg/24 hours or protein/creatinine ratio ≥0.3 mg/mg) or, in the absence of proteinuria, newonset maternal organ dysfunction (thrombocytopenia, renal insufficiency, impaired liver function, pulmonary oedema, or neurological symptoms). Preeclampsia was further classified as earlyonset (delivery <34 weeks) or lateonset (delivery ≥34 weeks). Outcome data were extracted from hospital delivery records and verified by the attending obstetrician. Statistical Data Analysis Data were entered in Microsoft Excel and analysed using SPSS version 26.0 (IBM Corp., USA). Continuous variables were tested for normality using the ShapiroWilk test. Normally distributed variables were presented as mean ± standard deviation and compared between groups using the independent samples ttest; skewed variables were expressed as median with interquartile range (IQR) and analysed with the MannWhitney U test. Categorical data were summarised as frequencies and percentages and compared using the chisquare test or Fisher’s exact test as appropriate. The predictive performance of uterine artery PI, PAPPA MoM, and their combination was assessed by receiver operating characteristic (ROC) curve analysis. Optimal cutoff values were determined using the Youden index. Sensitivity, specificity, PPV, and NPV were computed using 2×2 contingency tables. The area under the ROC curve (AUC) was reported with 95% confidence intervals. A binary logistic regression model was constructed to identify independent predictors of preeclampsia, with adjustments for potential confounders such as maternal age and BMI. A twotailed pvalue <0.05 was considered statistically significant.

A total of 24 pregnant women were recruited, and complete outcome data were available for all. The baseline characteristics of the study population are summarised in Table 1. The mean maternal age was 27.5 ± 4.2 years, the median BMI was 24.8 kg/m² (IQR 22.5–27.1), and 45.8% (n=11) were nulliparous. Preeclampsia developed in 8 women (33.3%), of whom 3 (12.5%) had early onset and 5 (20.8%) had late onset disease. The remaining 16 women (66.7%) remained normotensive throughout gestation. There were no significant differences in age, parity, or BMI between the preeclampsia and non preeclampsia groups, although the preeclampsia group tended to have a higher proportion of nulliparous women (62.5% vs. 37.5%, p=0.38). Table 1: Baseline characteristics of the study population (n=24) Variable Total (n=24) Preeclampsia (n=8) No Preeclampsia (n=16) p value Maternal age (years) 27.5 ± 4.2 28.1 ± 4.5 27.2 ± 4.1 0.63 Gestational age at scan (weeks) 12.4 ± 0.8 12.5 ± 0.7 12.3 ± 0.9 0.58 BMI (kg/m²) 24.8 (22.5–27.1) 25.4 (23.0–28.2) 24.6 (22.1–26.5) 0.29 Nulliparous, n (%) 11 (45.8) 5 (62.5) 6 (37.5) 0.38 Smokers, n (%) 0 (0) 0 (0) 0 (0) – Values are mean ± SD, median (IQR), or n (%). BMI: body mass index. The uterine artery Doppler parameters in the two groups are compared in Table 2. The mean uterine artery PI was significantly elevated in women who subsequently developed preeclampsia (2.18 ± 0.42 vs. 1.47 ± 0.31, p<0.001). Similarly, the mean RI was higher in the preeclampsia group (0.78 ± 0.08 vs. 0.65 ± 0.07, p<0.001). Bilateral diastolic notching was observed in 4 of the 8 women (50.0%) with preeclampsia compared with only 1 of the 16 (6.3%) in the unaffected group (p=0.016). The presence of any notching (unilateral or bilateral) was also more frequent in the preeclampsia group (75.0% vs. 18.8%, p=0.007). Figure 1 illustrates the stark difference in mean uterine artery PI between the two outcome groups. Table 2: Comparison of first trimester uterine artery Doppler indices between women with and without preeclampsia Doppler Parameter Preeclampsia (n=8) No Preeclampsia (n=16) p value Mean UtA-PI 2.18 ± 0.42 1.47 ± 0.31 <0.001 Mean UtA-RI 0.78 ± 0.08 0.65 ± 0.07 <0.001 Bilateral notching, n (%) 4 (50.0) 1 (6.3) 0.016 Any notching, n (%) 6 (75.0) 3 (18.8) 0.007 UtA-PI: uterine artery pulsatility index; UtA-RI: uterine artery resistance index. Serum PAPP A MoM values are presented in Table 3. The median PAPP A MoM in the preeclampsia group was 0.62 (IQR 0.48–0.81), significantly lower than the 1.12 MoM (IQR 0.89–1.34) recorded in the normotensive group (p=0.002). Low PAPP A (≤0.5 MoM) was found in 5 of 8 women (62.5%) with preeclampsia and in 3 of 16 women (18.8%) without the disease (p=0.037). The distribution of pregnancy outcomes is depicted in Figure 2, showing that one third of the cohort developed preeclampsia. Table 3: First trimester serum PAPP A levels PAPP A Parameter Preeclampsia (n=8) No Preeclampsia (n=16) p value PAPP A MoM, median (IQR) 0.62 (0.48–0.81) 1.12 (0.89–1.34) 0.002 PAPP A ≤0.5 MoM, n (%) 5 (62.5) 3 (18.8) 0.037 PAPP A: pregnancy associated plasma protein A; MoM: multiples of the median. The predictive performance of individual and combined markers is summarised in Table 4. When uterine artery mean PI >95th percentile (≥1.8) was used as a screening test, sensitivity was 75.0% and specificity 75.0%, with a PPV of 60.0% and an NPV of 85.7%. PAPP A ≤0.5 MoM alone gave a sensitivity of 62.5% and specificity of 81.3%. The combination of either marker positive (UtA-PI >95th percentile or PAPP A ≤0.5 MoM) raised the sensitivity to 87.5% and maintained specificity at 81.3%, with a PPV of 70.0% and an NPV of 92.9%. The AUC for mean UtA-PI alone was 0.82 (95% CI 0.64–0.99), for PAPP A alone 0.74 (95% CI 0.54–0.94), and for the combined model 0.84 (95% CI 0.68–1.00). Table 4: Predictive performance of first trimester uterine artery Doppler and PAPP A for preeclampsia Marker Sensitivity (%) Specificity (%) PPV (%) NPV (%) AUC (95% CI) UtA-PI >95th percentile (≥1.8) 75.0 75.0 60.0 85.7 0.82 (0.64–0.99) PAPP A ≤0.5 MoM 62.5 81.3 62.5 81.3 0.74 (0.54–0.94) Combined (UtA-PI or PAPP A) 87.5 81.3 70.0 92.9 0.84 (0.68–1.00) PPV: positive predictive value; NPV: negative predictive value; AUC: area under the ROC curve; CI: confidence interval. Table 5: Logistic regression analysis for prediction of preeclampsia Predictor Odds Ratio (95% CI) p value Mean UtA-PI (per 0.1 unit increase) 2.81 (1.28–6.18) 0.010 PAPP A MoM (per 0.1 unit decrease) 1.54 (1.06–2.24) 0.024 Nulliparity 2.10 (0.45–9.73) 0.347 BMI (per kg/m²) 1.12 (0.88–1.42) 0.355 Logistic regression analysis (Table 5) confirmed that mean UtA-PI and PAPP A were independent predictors of preeclampsia after adjusting for parity and BMI. Each 0.1 unit increase in mean UtA-PI was associated with a 2.81 fold increased risk of preeclampsia (95% CI 1.28–6.18, p=0.010), while each 0.1 unit decrease in PAPP A MoM increased the odds by 1.54 (95% CI 1.06–2.24, p=0.024). Nulliparity and BMI did not reach statistical significance in this small sample.

This prospective pilot study, conducted in a tertiary care hospital in Pune, India, demonstrates that both firsttrimester uterine artery Doppler indices and maternal serum PAPPA are significant predictors of preeclampsia. The mean uterine artery PI was 48% higher in women who later developed the disease, and the presence of bilateral notching was eight times more frequent in the preeclampsia group. Low PAPPA (≤0.5 MoM) also identified a substantial proportion of atrisk pregnancies. The combination of elevated UtA-PI and low PAPPA yielded a sensitivity of 87.5% and a negative predictive value of 92.9%, suggesting that a normal dualmarker screen can provide considerable reassurance, while a positive screen identifies a subset of women who may benefit from intensified surveillance and aspirin prophylaxis. The observed performance of uterine artery Doppler in our Indian cohort is consistent with the international literature. In a landmark study, Plasencia et al. reported that mean uterine artery PI above the 95th percentile at 11–13⁺⁶ weeks detected 40–70% of earlyonset preeclampsia, with a specificity of approximately 90% [2]. A systematic review by Cnossen et al. confirmed that increased firsttrimester uterine artery impedance is a strong predictor of preeclampsia, especially when diastolic notching is present [20]. Our sensitivity of 75% for UtA-PI >95th percentile lies within this range, despite our notably smaller sample. The higher proportion of bilateral notching in the preeclampsia group (50% vs 6.3%) reinforces the pathophysiological link between impaired trophoblastic invasion and abnormal Doppler waveforms. However, it should be noted that the relatively high background incidence of preeclampsia in our cohort (33%) likely reflects the referral pattern of a tertiary hospital and limits the generalisability of absolute predictive values to lowrisk populations. PAPPA emerged as a valuable biochemical marker in our study. The median MoM of 0.62 in the preeclampsia group is remarkably similar to values reported by Spencer et al. and Dugoff et al., who found that PAPPA below the 5th percentile (∼0.4–0.5 MoM) conferred a two to fourfold increase in risk [8,13]. The metaanalysis by Zhong et al. demonstrated that low PAPPA in the first trimester was associated with a pooled odds ratio of 2.3 for preeclampsia, underscoring its consistent, albeit modest, predictive ability [14]. Our logistic regression model identified PAPPA as an independent predictor, with a 1.54fold increase in odds per 0.1 MoM decrease. Interestingly, while low PAPPA alone detected 62.5% of preeclampsia cases, it also generated a falsepositive rate of 18.8%. This moderate specificity is comparable to published data and highlights the need for combination with biophysical markers to improve screening performance [16]. The combined screening strategy using either an elevated UtA-PI or low PAPPA achieved the highest sensitivity (87.5%) and an AUC of 0.84, which is in line with prediction models from large multicentre studies. For instance, the FMF competingrisks model, which incorporates maternal factors, mean arterial pressure, UtA-PI, and PAPPA, has demonstrated detection rates of 75–90% for preterm preeclampsia at a 10% falsepositive rate [9,11]. Our simplified twomarker approach, without mean arterial pressure, still performed well, detecting almost 9 out of 10 cases. The negative predictive value of 92.9% is particularly encouraging; a woman with both markers in the normal range could be classified as low risk, potentially reducing unnecessary anxiety and interventions. The PPV of 70% indicates that a positive screen is clinically meaningful and could guide the initiation of aspirin 150 mg at bedtime a regimen shown to reduce preterm preeclampsia by 62% in the ASPRE trial [5]. Importantly, both UtA Doppler and PAPPA are already part of the standard firsttrimester aneuploidy screening in many Indian centres, meaning that preeclampsia risk assessment can be added with minimal extra cost and time. Despite these promising results, several considerations must temper the interpretation of our findings. The high preeclampsia incidence in our sample partly explained by the high proportion of nulliparous women and the referral nature of the hospital might overestimate the screening performance when applied to an unselected, lowrisk population. The sample size of 24 women, while sufficient for a pilot evaluation, limits the precision of the estimates, as evidenced by the wide confidence intervals around the odds ratios and the AUC. Moreover, earlyonset and lateonset preeclampsia were not analysed separately due to the small number of cases, even though screening tests are generally more effective for preterm disease [4]. The absence of maternal serum placental growth factor (PlGF), a marker now incorporated into many prediction algorithms [18], is another limitation. Finally, all Doppler examinations were performed by a single experienced operator, which may not reflect the variability encountered in routine clinical settings. The strengths of the study include its prospective design, stringent adherence to FMF Doppler protocols, and complete followup of all enrolled participants. The use of widely available and standardised assays for PAPPA enhances the external validity. This study is one of the few from Western India to specifically examine the combined predictive value of UtA Doppler and PAPPA in the first trimester, contributing valuable local data. It reinforces the feasibility of integrating preeclampsia screening into the existing antenatal care infrastructure, paving the way for larger validation studies and eventual implementation of a onestop risk assessment clinic. Limitations of the Study The small sample size of 24 women is the principal limitation, precluding robust subgroup analyses such as prediction of early versus lateonset preeclampsia, and giving rise to wide confidence intervals for the diagnostic accuracy estimates. The study was conducted in a single tertiary referral centre with a highrisk obstetric population, which inflates the preeclampsia rate to 33% and limits the generalisability of positive predictive values to primary care settings. All ultrasound examinations were performed by one FMFcertified sonographer, so interoperator variability and the realworld reproducibility of Doppler measurements could not be assessed. The study did not include maternal serum placental growth factor (PlGF) or mean arterial pressure, both of which are known to enhance screening performance. In addition, the observational design meant that aspirin was not administered based on screening results, precluding evaluation of the clinical impact of the prediction strategy on pregnancy outcomes. Finally, the research period of 10 months was relatively short, and seasonal or temporal variations in PAPPA levels could not be examined. Acknowledgment The authors are grateful to the Department of Obstetrics and Gynaecology and the staff of the antenatal clinic and laboratory at the study hospital for their unwavering support and cooperation. We sincerely thank all the women who participated in this study, generously giving their time and consent during a busy period of their pregnancy. The study received no specific funding from any public, commercial, or notforprofit agency; it was conducted as part of routine academic research. We also acknowledge the Fetal Medicine Foundation for the training and certification provided to the sonographer, which ensured the quality of Doppler measurements.

This prospective pilot study confirms that firsttrimester uterine artery Doppler and maternal serum PAPPA are significant and independent predictors of preeclampsia in an Indian tertiary care setting. The combination of elevated mean uterine artery PI and low PAPPA (≤0.5 MoM) achieved a clinically meaningful sensitivity of 87.5% and a negative predictive value of 92.9%, while maintaining a specificity of 81.3%. These findings align with a robust body of international evidence and highlight the potential of a simple, dualmarker screening strategy that can be seamlessly integrated into existing firsttrimester aneuploidy programmes. The high NPV suggests that a normal screen can reliably identify lowrisk women, whereas a positive screen warrants timely initiation of aspirin and intensified antenatal surveillance, consistent with current clinical guidelines. Larger, multicentre studies across diverse Indian populations are essential to validate these results, establish populationspecific cutoffs, and assess the costeffectiveness of adding PlGF and mean arterial pressure to the screening algorithm. The ultimate goal is to develop a pragmatic, accessible, and scalable firsttrimester screening tool that reduces the burden of preeclampsia through early risk stratification and prophylactic intervention. Until such evidence is available, the present data support the cautious implementation of uterine artery Doppler and PAPPA as part of a riskassessment package in tertiary Indian centres, offering a valuable step toward improving maternal and perinatal outcomes in the region.

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