Preeclampsia is a pregnancy-specific hypertensive disorder and a major contributor to maternal and perinatal morbidity and mortality, particularly in low- and middle-income countries such as India. The condition is characterized by widespread endothelial dysfunction and abnormal placentation resulting from defective trophoblastic invasion and incomplete remodeling of the uterine spiral arteries. These vascular abnormalities lead to maternal vascular malperfusion, placental hypoxia, and subsequent impairment of fetoplacental exchange, which clinically manifest as hypertension, proteinuria, and fetal growth restriction. In normal gestation, the uterine spiral arteries undergo physiological transformation into dilated, low-resistance channels that ensure continuous perfusion of the intervillous space. In preeclampsia, this remodeling is shallow or incomplete, resulting in intermittent perfusion and ischemia–reperfusion injury. Gutierrez et al. (2020) [1] demonstrated that aberrant protease activity impairs extracellular matrix remodeling necessary for vascular transformation, while Travaglino et al. (2019) [2] reported increased apoptosis and diminished angiogenesis in early-onset preeclampsia. Structural studies by Shchegolev et al. (2018) [3] have also highlighted villous hypovascularity and stromal fibrosis as morphological hallmarks of the disorder, reflecting chronic hypoxic injury. Molecular investigations have identified an imbalance between angiogenic and antiangiogenic factors—particularly elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and reduced placental growth factor (PlGF)—as a major contributor to vascular dysfunction. Wu et al. (2020) [4] demonstrated that restoring angiogenic balance through heme oxygenase-1–modified stem cells may enhance placental angiogenesis and spiral artery remodeling, underscoring the mechanistic link between molecular signalling and structural pathology. Although intrauterine growth restriction (IUGR) and preeclampsia share certain histopathological features, morphometric studies suggest differing mechanisms. Mayhew et al. (2004) [5] showed that fetoplacental angiogenesis is markedly reduced in IUGR, whereas maternal vascular maladaptation predominates in preeclampsia. Moreover, systemic maternal vascular conditions have been shown to affect placental angiogenesis, as observed by Ortega et al. (2020) [6] in pregnancies complicated by chronic venous disease. Literature gap and rationale: Despite growing international research, there is a paucity of Indian data providing quantitative histomorphological assessment of placental vascular patterns in preeclampsia. Most local studies remain descriptive, lacking standardization of morphometric parameters such as villous capillary count, vessel density, or spiral artery remodeling score. Given India’s regional diversity in nutritional, genetic, and environmental factors influencing pregnancy outcomes, establishing normative and pathological reference data is essential. Hence, the present study aims to conduct a comparative histomorphological evaluation of placental vascular architecture in normal and preeclamptic pregnancies in an eastern Indian population. By correlating measurable vascular indices with maternal and fetal outcomes, this study seeks to elucidate structural correlates of maternal vascular malperfusion and contribute to the development of standardized morphometric criteria for placental evaluation in hypertensive disorders of pregnancy Objectives Primary Objective To perform a comparative histomorphological evaluation of placental vascular patterns in normal and preeclamptic pregnancies, focusing on quantitative parameters of villous vascularity and maternal vascular remodeling. Secondary Objectives 1. To quantify key placental vascular indices—including capillaries per terminal villus, vessel density, syncytial knot percentage, perivillous fibrin deposition, and proportion of avascular villi—in both study groups. 2. To assess spiral artery remodeling in relation to villous vascularity and determine its degree of alteration in preeclampsia. 3. To analyze correlations between histomorphological parameters and perinatal outcomes, particularly placental weight and fetal birthweight. 4. To develop an exploratory multivariable model evaluating the combined diagnostic utility of histomorphological markers in differentiating preeclampsia from normal pregnancy.

Study Design and Setting This was a hospital-based, cross-sectional comparative study conducted over a period of one year (January 2024–December 2024) in the Department of Pathology, Gouri Devi Institute of Medical Sciences and Hospital, Durgapur, West Bengal, India, in collaboration with the Department of Obstetrics and Gynaecology. The study aimed to compare histomorphological vascular patterns of placentas obtained from normal and preeclamptic pregnancies. Study Population and Sample Size A total of 50 placentas were examined, comprising 25 from normotensive pregnancies (control group) and 25 from preeclamptic pregnancies (study group). The sample size was determined based on feasibility during the study period and comparable to previously published morphometric studies in placental pathology. Inclusion Criteria • Singleton pregnancies delivered at ≥34 weeks of gestation. • Control group: normotensive mothers without proteinuria or systemic disease. • Study group: clinically diagnosed preeclampsia, defined as blood pressure ≥140/90 mmHg after 20 weeks of gestation with proteinuria ≥300 mg/24 h, or presence of other systemic features consistent with preeclampsia, as per ACOG 2020 criteria. Exclusion Criteria • Multiple gestations. • Pregnancies with known fetal anomalies or intrauterine fetal demise. • Mothers with chronic hypertension, diabetes mellitus, renal disease, or connective tissue disorders. • Placentae showing extensive autolysis or maceration. Specimen Collection and Gross Examination Immediately after delivery, the placenta was collected, washed in running water, and membranes and cord trimmed at the point of insertion. The fresh weight of the placenta was recorded using a digital weighing scale after draining excess blood. Gross examination noted the shape, completeness, cord insertion, infarcts, and calcification. Representative sections (approximately 2×2 cm) were taken from central and peripheral regions, as well as from any grossly abnormal areas. Tissue Processing and Histological Evaluation Tissue samples were fixed in 10% neutral buffered formalin, processed through routine paraffin embedding, and sectioned at 4–5 µm thickness. Slides were stained with Haematoxylin and Eosin (H&E) and examined under a light microscope. Quantitative and semi-quantitative parameters were evaluated as follows: Parameter Definition / Method of Assessment Capillaries per terminal villus (CPV) Mean number of vascular profiles counted in ≥20 well-formed terminal villi per case. Vessel density (per mm²) Average vessel count from three 400× “hot-spot” fields using calibrated eyepiece grid. Syncytial knots (%) Percentage of terminal villi showing ≥3 aggregated syncytial nuclei per high-power field. Perivillous fibrin (% area) Estimated proportion of fibrinoid deposition in the intervillous/perivillous space. Avascular villi (%) Proportion of terminal villi devoid of vascular channels. Spiral artery remodeling score (0–3) 0 = absent, 1 = partial, 2 = substantial, 3 = complete physiologic change. Categorical features such as villous infarction, chorangiosis, and cord abnormalities (marginal, velamentous insertion, or true knots) were also recorded. Outcome Variables The primary outcome was the difference in villous vascularity and spiral artery remodeling between normal and preeclamptic placentas. Secondary outcomes included correlations of vascular parameters with placental weight and fetal birthweight, as well as exploratory modelling for diagnostic discrimination of preeclampsia. Statistical Analysis Data were compiled and analyzed using SPSS version 26.0 (IBM Corp., USA). Continuous variables were tested for normality using the Shapiro–Wilk test and expressed as mean ± standard deviation (SD). Between-group comparisons were performed using the independent samples t-test (Welch correction applied when variances were unequal). Non-parametric equivalents (Mann–Whitney U test) were applied where appropriate. Categorical variables were analyzed using the Chi-square test or Fisher’s exact test Correlations between continuous variables were assessed using Pearson’s correlation coefficient (r). Effect sizes were reported as Cohen’s d, and a two-tailed p-value <0.05 was considered statistically significant. An exploratory binary logistic regression model was applied to assess the discriminative potential of selected histomorphological parameters, with results summarized by area under the ROC curve (AUC). Ethical Considerations This study was conducted in accordance with the Declaration of Helsinki (2013). Institutional Ethics Committee approval was obtained prior to study initiation.

1. Baseline Maternal and Perinatal Characteristics A total of 50 placentas were examined, comprising 25 from normotensive pregnancies (control group) and 25 from preeclamptic pregnancies (study group). The baseline maternal and perinatal characteristics are presented in Table 1. The mean maternal age did not differ significantly between the two groups (24.83 ± 3.98 years vs. 26.36 ± 4.63 years; p = 0.216). However, pregnancies complicated by preeclampsia showed a significantly lower mean gestational age at delivery (36.67 ± 1.36 weeks) compared with normotensive pregnancies (39.13 ± 1.08 weeks; p < 0.001). The mean placental weight and neonatal birthweight were also significantly reduced in the preeclamptic group (419.40 ± 80.92 g and 2461.76 ± 471.91 g, respectively) compared to controls (523.80 ± 72.15 g and 3100.60 ± 299.49 g; both p < 0.001).No maternal comorbidities or fetal anomalies were noted in either group. Table 1. Baseline maternal and perinatal characteristics in normal and preeclamptic pregnancies (N = 50) Variable Normal (n = 25) Mean ± SD Preeclampsia (n = 25) Mean ± SD p-value Maternal age (years) 24.83 ± 3.98 26.36 ± 4.63 0.216 Gestational age (weeks) 39.13 ± 1.08 36.67 ± 1.36 < 0.001 Placental weight (g) 523.80 ± 72.15 419.40 ± 80.92 < 0.001 Birthweight (g) 3100.60 ± 299.49 2461.76 ± 471.91 < 0.001 2. Quantitative Histomorphological Parameters Quantitative evaluation of villous vascularity and stromal indices revealed statistically significant differences between the two groups (Table 2). The mean number of capillaries per terminal villus was significantly lower in preeclamptic placentas (4.40 ± 0.76) compared with normal placentas (5.81 ± 0.85; p < 0.001). Vessel density per mm² also showed a significant reduction in the preeclampsia group (94.41 ± 20.00) relative to controls (117.07 ± 18.00; p = 0.0003). Syncytial knot formation was higher in preeclamptic placentas (30.44 ± 5.84%) than in normal placentas (19.56 ± 4.59%; p < 0.001). Similarly, the percentage of perivillous fibrin deposition and avascular villi was significantly increased in the preeclampsia group (22.10 ± 6.89% and 8.00 ± 2.78%, respectively) compared with controls (13.60 ± 3.88% and 2.81 ± 1.73%; both p < 0.001). The mean spiral artery remodeling score was lower among preeclamptic cases (1.49 ± 0.51) than in normal pregnancies (2.23 ± 0.43; p < 0.001). The endothelial nitric oxide synthase (eNOS) immunoreactivity score demonstrated a decreasing trend in preeclampsia (142.00 ± 45.49) compared to controls (163.84 ± 42.49), though the difference was not statistically significant (p = 0.086). Table 2. Quantitative placental vascular metrics in normal and preeclamptic pregnancies (N = 50) Parameter Normal (n = 25) Mean ± SD Preeclampsia (n = 25) Mean ± SD p-value Capillaries per terminal villus 5.81 ± 0.85 4.40 ± 0.76 < 0.001 Vessel density per mm² 117.07 ± 18.00 94.41 ± 20.00 0.0003 Syncytial knots (%) 19.56 ± 4.59 30.44 ± 5.84 < 0.001 Perivillous fibrin (% area) 13.60 ± 3.88 22.10 ± 6.89 < 0.001 Avascular villi (%) 2.81 ± 1.73 8.00 ± 2.78 < 0.001 Spiral artery remodeling score (0–3) 2.23 ± 0.43 1.49 ± 0.51 < 0.001 eNOS H-score (0–300) 163.84 ± 42.49 142.00 ± 45.49 0.086 3. Categorical Histopathological Findings The frequency of major categorical histopathological features is presented in Table 3. Villous infarction was observed in 12 (48%) preeclamptic placentas and 6 (24%) control placentas; this difference did not reach statistical significance (p = 0.141). Chorangiosis was identified in 7 (28%) cases of preeclampsia compared with 1 (4%) in the control group, a difference that was statistically significant (p = 0.049). Umbilical cord abnormalities, including marginal or velamentous insertion and true knots, were observed in 5 (20%) of preeclamptic and 3 (12%) of normal placentas, showing no significant difference between groups (p = 0.702). Table 3. Frequency of categorical histopathological features in normal and preeclamptic placentas (N = 50) Feature Normal (n = 25) n (%) Preeclampsia (n = 25) n (%) Statistical Test p-value Villous infarction 6 (24.0) 12 (48.0) Chi-square 0.141 Chorangiosis 1 (4.0) 7 (28.0) Fisher’s exact 0.049 Cord abnormality 3 (12.0) 5 (20.0) Fisher’s exact 0.702 4. Correlation Analyses Correlation analyses between quantitative histomorphological parameters and perinatal outcomes are summarized in Table 4.and showed in figure 1. Birthweight showed a significant positive correlation with the mean number of capillaries per terminal villus (r = 0.393, p = 0.005) and vessel density per mm² (r = 0.125, p = 0.387), although the latter did not reach statistical significance.A significant negative correlation was observed between birthweight and both syncytial knot percentage (r = −0.343, p = 0.015) and perivillous fibrin deposition (r = −0.402, p = 0.004). Spiral artery remodeling score demonstrated a modest positive correlation with vessel density (r = 0.291, p = 0.041). Table 4. Correlation coefficients (r) between histomorphological parameters and perinatal outcomes (N = 50) Variables Correlated Pearson’s r p-value Capillaries per terminal villus × Birthweight 0.393 0.005 Vessel density per mm² × Birthweight 0.125 0.387 Syncytial knots (%) × Birthweight −0.343 0.015 Perivillous fibrin (% area) × Birthweight −0.402 0.004 Spiral artery remodeling score × Vessel density 0.291 0.041 5. Exploratory Multivariable and Effect Size Analysis An exploratory logistic regression model was fitted to classify preeclampsia using standardized predictors (per 1 SD): capillaries per terminal villus, syncytial knots (%), perivillous fibrin (% area), spiral artery remodeling score, and gestational age (weeks). Model performance and coefficients are summarized in Table 5. Overall discrimination was high with AUC = 0.985 (95% CI, 0.958–1.000), shown in Figure 2. Nagelkerke R² = 0.86; Hosmer–Lemeshow goodness-of-fit p = 0.62. At a probability threshold of 0.50, apparent accuracy was 94% (sensitivity 96%, specificity 92%). Table 5. Exploratory logistic regression for classification of preeclampsia (standardized predictors; N = 50) Predictor (per 1 SD) OR 95% CI p-value Capillaries per terminal villus 0.21 0.08–0.52 0.001 Syncytial knots (%) 4.10 2.00–9.10 <0.001 Perivillous fibrin (% area) 2.05 1.10–4.00 0.024 Spiral artery remodeling score (0–3) 0.28 0.11–0.66 0.004 Gestational age (weeks) 0.19 0.07–0.50 0.001 Model summary: AUC = 0.985 (95% CI, 0.958–1.000); Nagelkerke R² = 0.86; Hosmer–Lemeshow p = 0.62; Apparent accuracy = 94% at threshold 0.50.

The present study demonstrates that placentas from preeclamptic pregnancies exhibit distinct and quantifiable vascular abnormalities, including reduced villous vascularity, increased syncytial knot formation, and impaired spiral artery remodeling. These findings are consistent with the pathological spectrum of maternal vascular malperfusion (MVM) described in recent literature [7–16]. Horii et al. (2023) integrated histopathologic and transcriptomic profiling to reveal novel trophoblastic defects and failed vascular remodeling in preeclamptic placentas [7]. Their molecular evidence of altered trophoblast differentiation parallels our morphometric findings, where the mean capillaries per terminal villus were significantly reduced (4.40 ± 0.76 vs. 5.81 ± 0.85; p < 0.001), reflecting impaired villous angiogenesis. Likewise, Weiner et al. (2018) demonstrated that placentas from preeclampsia with severe features had a twofold higher incidence of distal villous hypoplasia and infarction (47% vs. 23%), corresponding closely with our observation of infarction in 48% of preeclamptic cases [8]. Afsar et al. (2023) observed that fetal vascular malperfusion (FVM) scores were significantly higher in preeclamptic pregnancies with gestational diabetes (mean 3.2 ± 1.1 vs. 1.6 ± 0.7; p < 0.01) [9]. Although diabetic cases were excluded in our study, the increased proportion of avascular villi (8.0 ± 2.78% vs. 2.81 ± 1.73%) suggests similar downstream effects on the fetoplacental vasculature. Schiffer et al. (2021) provided further mechanistic insight, demonstrating that first-trimester angiogenic marker derangements (low PlGF and elevated sFlt-1) predicted later MVM-type lesions with an odds ratio of 3.6 (95% CI: 2.1–6.0) [10]. These biochemical findings are mirrored histologically in our data by significantly reduced spiral artery remodeling scores (1.49 ± 0.51 vs. 2.23 ± 0.43; p < 0.001). Dahlstrom et al. (2021) emphasized that the MVM spectrum includes villous infarction, increased syncytial knots, and distal villous hypoplasia, forming the prototypical placental phenotype of hypertensive disorders [11]. Our findings—syncytial knots at 30.44 ± 5.84% compared with 19.56 ± 4.59% in controls—fit within this diagnostic framework. Similarly, Dankó et al. (2023) correlated placental lesion burden with clinical severity, noting that placentas with fibrinoid necrosis exceeding 20% of villous area were associated with neonatal birthweight <2500 g in 56% of cases [12]. In our cohort, perivillous fibrin deposition averaged 22.1 ± 6.9%, consistent with their threshold for growth-restrictive pathology. In contrast, Visser et al. (2021) reported that MVM lesions in spontaneous preterm births were not always associated with adverse neonatal outcomes, suggesting a possible adaptive compensatory mechanism in certain cases [13]. This contrasts with our findings, where birthweight correlated negatively with syncytial knots (r = −0.34, p = 0.015), implying persistent pathological rather than adaptive remodeling. Similarly, Stanek (2025) described overlapping histological features of maternal diabetes–related FVM and preeclampsia, concluding that both conditions share downstream ischemic signatures but differ in the initiating maternal vascular pathology [14]. Our exploratory logistic regression model yielded an AUC of 0.985, closely aligning with Weiner et al. (2016), who demonstrated that composite placental lesion indices predicted recurrence of preeclampsia with AUC values between 0.90 and 0.96 [15]. The model’s key predictors—syncytial knots (OR = 4.10, 95% CI: 2.00–9.10) and capillaries per terminal villus (OR = 0.21, 95% CI: 0.08–0.52)—underscore the quantitative histopathological utility of these markers in identifying high-risk placental phenotypes. Kutllovci Hasani et al. (2025) summarized that preeclampsia represents a multisystem disorder of cardiovascular–placental maladaptation, integrating hemodynamic and histopathological pathways [16]. Our data support this conceptual framework, highlighting that the morphological changes observed—reduced vascular density, increased hypoxic stress markers, and defective arterial remodeling—constitute the structural correlates of this maladaptation. Despite general concordance with global literature, regional differences must be recognized. Studies from Western populations often report later-onset and milder histological lesions [8,13], whereas Indian and South Asian studies, including the present one, frequently document earlier-onset disease with pronounced vascular pathology. Environmental factors such as nutritional anemia, chronic low-grade hypoxia, and genetic polymorphisms in angiogenic genes may influence this variation. Methodological factors—especially sampling location, section thickness, and observer variability—can also account for reported discrepancies in morphometric values. Limitations The main limitations of this study include its modest sample size, single-centre design, and absence of molecular correlation (e.g., angiogenic markers such as PlGF, VEGF, or sFlt-1). Although an exploratory logistic model demonstrated high discrimination, internal validation alone cannot exclude overfitting. Future multicentric studies integrating digital morphometry and serum angiogenic profiling across diverse Indian populations are warranted to refine histomorphological cutoffs and validate their prognostic value.

Preeclampsia is characterized by a reproducible pattern of maternal vascular malperfusion and villous hypovascularity, reflecting defective trophoblastic remodeling and impaired fetoplacental perfusion. In this study, preeclamptic placentas exhibited significantly reduced villous vascularity, increased syncytial knots, enhanced perivillous fibrin deposition, and lower spiral artery remodeling scores compared with normal pregnancies. Quantitative parameters such as capillaries per terminal villus and syncytial knot percentage emerged as strong histomorphological discriminators, with an exploratory model demonstrating excellent diagnostic performance (AUC = 0.985). These findings reinforce the value of standardized morphometric evaluation in elucidating the structural correlates of placental dysfunction. Larger multicentric studies integrating molecular and digital morphometric analyses are recommended to establish normative reference ranges and enhance diagnostic reproducibility in the assessment of hypertensive disorders of pregnancy.

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