Perinatal anxiety and depressive symptoms in women with preeclampsia: A cohort study of placental dysfunction and neuroendocrine correlates

Abstract

BACKGROUND

Preeclampsia is associated with a markedly increased risk of perinatal mental health disorders; however, the biological mechanisms underlying this association remain poorly defined. Emerging evidence suggests that placental dysfunction and altered neuroendocrine stress responses contribute to increased psychological vulnerability in affected women.

AIM

To investigate associations between placental dysfunction biomarkers, neuroendocrine dysregulation, and the severity of perinatal anxiety and depressive symptoms in preeclampsia.

METHODS

This prospective study (October 2022-October 2025) included 210 pregnant women: (1) 105 diagnosed with preeclampsia; and (2) 105 normotensive controls. Participants completed the Edinburgh Postnatal Depression Scale (EPDS), Generalized Anxiety Disorder-7 (GAD-7), and State-Trait Anxiety Inventory at enrollment, during the third trimester, and at 6 weeks postpartum. Maternal serum soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), the sFlt-1/PlGF ratio, and salivary cortisol (hypothalamic-pituitary-adrenal axis activity) were measured, alongside clinical indicators, including blood pressure, proteinuria, and obstetric outcomes.

RESULTS

Compared with normotensive controls, women with preeclampsia exhibited significantly higher psychological distress, with elevated EPDS (12.8 ± 5.4 vs 6.2 ± 3.1, P < 0.001), GAD-7 (10.3 ± 4.2 vs 5.1 ± 2.8, P < 0.001), and State-Trait Anxiety Inventory-State scores (44.6 ± 9.8 vs 32.4 ± 7.2, P < 0.001). Clinically significant anxiety was more prevalent in the preeclampsia group (61.9% vs 18.1%, P < 0.001). The sFlt-1/PlGF ratios correlated positively with EPDS (r = 0.42) and GAD-7 (r = 0.38) scores (P < 0.001). Morning salivary cortisol was elevated in women with preeclampsia and depressive symptoms compared to those without depression (18.7 ± 4.3 nmol/L vs 14.2 ± 3.1 nmol/L, P = 0.002). Multivariable regression identified the sFlt-1/PlGF ratio (β = 0.28, P = 0.003), morning cortisol (β = 0.31, P = 0.001), and disease severity (β = 0.35, P < 0.001) as independent predictors of depressive symptom severity.

CONCLUSION

Preeclampsia is associated with increased perinatal anxiety and depressive symptoms, potentially mediated by placental dysfunction and hypothalamic-pituitary-adrenal axis activation, underscoring the need for integrated obstetric-psychiatric screening and early intervention.

Key Words: Preeclampsia; Perinatal depression; Anxiety; Placental biomarkers; Soluble fms-like tyrosine kinase-1/placental growth factor ratio; Cortisol; Hypothalamic-pituitary-adrenal axis

Core Tip: This study highlights the strong association between preeclampsia and elevated perinatal anxiety and depressive symptoms, emphasizing the need for integrated obstetric-psychiatric care. By simultaneously assessing placental dysfunction biomarkers and neuroendocrine stress indicators, the study provides novel evidence for biological pathways linking preeclampsia with mental health vulnerability. Elevated soluble fms-like tyrosine kinase-1/placental growth factor ratios and increased morning cortisol were independently correlated with symptom severity, suggesting potential value in early risk stratification. These findings underscore the importance of routine psychological screening during pregnancy complicated by preeclampsia and support the development of targeted interventions to improve maternal mental health outcomes.

INTRODUCTION

Preeclampsia is a pregnancy-specific multisystem disorder characterized by new-onset hypertension and end-organ dysfunction after 20 weeks of gestation, affecting approximately 2%-8% of pregnancies worldwide[1,2]. Beyond its immediate obstetric complications, preeclampsia has been increasingly recognized as a significant risk factor for maternal psychological morbidity during the perinatal period[3]. The intersection between this major hypertensive disorder of pregnancy and maternal mental health represents a critical yet underexplored area in perinatal medicine.

Perinatal mental health disorders, including depression and anxiety, affect approximately 10%-20% of pregnant and postpartum women in the general population[4]. However, emerging evidence suggests that women with preeclampsia are at substantially elevated risk. Recent studies have demonstrated that preeclampsia is associated with a 53% increased risk of antenatal depressive symptoms[5], and women admitted to hospitals with severe preeclampsia show significantly higher levels of both anxiety and depression than those with uncomplicated pregnancies[6]. The American College of Obstetricians and Gynecologists recommends routine screening for perinatal mood and anxiety disorders, recognizing their profound impact on maternal and infant wellbeing[7].

However, the pathophysiological mechanisms linking preeclampsia to perinatal mental health disorders remain unclear. Preeclampsia is a fundamental disorder of placental dysfunction characterized by inadequate spiral artery remodeling, placental hypoxia, and the release of anti-angiogenic factors into the maternal circulation[8]. The soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio has emerged as a key biomarker of placental dysfunction and is now Food and Drug Administration-approved for risk stratification of suspected preeclampsia[9]. Elevated sFlt-1 levels and decreased PlGF concentrations reflect the anti-angiogenic state that underlies both early-onset and late-onset forms of the disease[10]. However, whether these placental biomarkers are associated with psychological symptoms has not been systematically investigated.

Another potential mechanism is neuroendocrine dysregulation. The hypothalamic-pituitary-adrenal (HPA) axis undergoes substantial changes during normal pregnancy, with cortisol levels increasing approximately three-fold by the third trimester[11]. Psychological stress and depression are associated with HPA axis dysfunction, which is characterized by altered cortisol secretion patterns[12]. Some researchers have proposed that distress during pregnancy may contribute to the development of preeclampsia by enhancing cortisol levels, which are associated with hypertension and endothelial dysfunction[13]. However, the direction of the relationship remains unclear. Understanding whether preeclampsia itself induces neuroendocrine changes that predispose individuals to mental health symptoms can inform both screening protocols and therapeutic interventions.

The relationship between anxiety, depression, and preeclampsia appears to be bidirectional. Although prenatal anxiety and depression have been identified as risk factors for developing hypertensive disorders during pregnancy[14], the diagnosis of preeclampsia itself represents a significant stressor that may precipitate or exacerbate psychological symptoms[15]. The complexity of this relationship necessitates comprehensive assessment of both biological and psychological factors across the perinatal continuum. Despite growing recognition of the association between preeclampsia and perinatal mental health disorders, significant gaps remain in our understanding. Most existing studies are cross-sectional, which limits their ability to assess temporal relationships. Few studies have comprehensively examined both anxiety and depression, and even fewer have investigated their potential biological correlations, such as placental biomarkers and stress hormones. Additionally, the postpartum period represents a vulnerable time for both persistent preeclampsia-related complications and mental health deterioration, yet longitudinal follow-up data are sparse. The present study aimed to address these gaps through a prospective study design examining women with preeclampsia and normotensive controls across the perinatal period.

MATERIALS AND METHODS

Study design and setting

This prospective study was conducted at Maternal and Child Health Care Hospital of Shandong Provincial from October 2022 to October 2025. The study protocol was approved by the Institutional Review Board and all participants provided written informed consent. Women were recruited from the hospital's obstetric clinics and antepartum units, with enrollment occurring at the time of preeclampsia diagnosis for cases or during routine third-trimester visits for controls.

Participants

A total of 210 pregnant women were enrolled, comprising 105 women diagnosed with preeclampsia and 105 normotensive pregnant controls matched for gestational age at enrollment. The preeclampsia group was further subdivided into early-onset preeclampsia (diagnosed < 34 weeks, n = 28) and late-onset preeclampsia (diagnosed ≥ 34 weeks, n = 77) based on established criteria reflecting distinct pathophysiological profiles. Women in the control group were selected from among those attending routine prenatal care, with careful matching to ensure comparable demographic characteristics and gestational timing.

Inclusion criteria for the preeclampsia group: (1) Singleton pregnancy; (2) Gestational age ≥ 20 weeks; (3) New-onset hypertension defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg on at least two occasions measured at least 4 hours apart; (4) Proteinuria ≥ 300 mg per 24-hour urine collection or protein/creatinine ratio ≥ 0.3, or in the absence of proteinuria, new-onset hypertension with signs of maternal end-organ dysfunction including thrombocytopenia (platelet count < 100000/μL), elevated liver enzymes (transaminases > 2 times upper limit of normal), renal insufficiency (serum creatinine > 1.1 mg/dL or doubling of serum creatinine), pulmonary edema, or cerebral or visual symptoms; (5) Age 18-45 years; and (6) Ability to provide informed consent and complete questionnaires in the local language.

Inclusion criteria for the control group: (1) Singleton pregnancy; (2) Gestational age matched to preeclampsia cases (± 2 weeks); (3) Normotensive blood pressure throughout pregnancy (< 140/90 mmHg); (4) Absence of proteinuria or other signs of pregnancy complications; (5) Age 18-45 years; and (6) Ability to provide informed consent and complete questionnaires.

Exclusion criteria for both groups: (1) Multiple gestation; (2) Chronic hypertension predating pregnancy or diagnosed before 20 weeks gestation; (3) Known renal disease, autoimmune disorders, or other chronic medical conditions that could confound the relationship between preeclampsia and mental health outcomes; (4) Current use of psychotropic medications or medications known to affect cortisol levels including systemic corticosteroids; (5) Diagnosed psychiatric disorder requiring ongoing treatment prior to current pregnancy; (6) Substance abuse during pregnancy; (7) Fetal anomalies or known chromosomal abnormalities; (8) Inability to complete study questionnaires due to language barriers or cognitive limitations; and (9) Women who declined to participate or withdrew consent during the study period.

Data collection and follow-up

Data were collected at three time points: (1) Enrollment (at diagnosis of preeclampsia for cases or matched gestational age for controls); (2) Late third trimester (34-37 weeks of gestation); and (3) 6 weeks postpartum. At each visit, participants completed psychological assessment questionnaires, provided biological samples, and underwent clinical evaluations. Research personnel trained in standardized data collection procedures conducted all the assessments. To minimize bias, personnel administering psychological questionnaires were blinded to the participants' biomarker results, whereas laboratory personnel analyzing biological samples were blinded to the psychological assessment scores.

The timing of the assessments was designed to capture the trajectory of psychological symptoms across critical perinatal periods. The enrollment assessment established the baseline psychological status at the time of preeclampsia diagnosis or matched gestational age. The late third-trimester assessment occurred during the period of maximal physiological stress and disease progression in patients with preeclampsia. The 6-week postpartum assessment evaluated the persistence or resolution of symptoms following delivery, which represents the definitive treatment for preeclampsia but also a vulnerable period for postpartum mental health disorders.

Psychological assessments

All participants completed a comprehensive battery of validated psychological assessment instruments at each time point. These assessments were self-administered under the supervision of research staff, who were available to answer questions and ensure complete responses.

The Edinburgh Postnatal Depression Scale (EPDS) is a primary measure of depressive symptoms. This 10-item self-report questionnaire has been extensively validated for use during pregnancy and the postpartum period, demonstrating sensitivity and specificity for detecting major depressive disorders in perinatal populations. Items assessed feelings experienced over the past seven days, with responses scored on a 4-point scale (0-3). The total scores range from 0 to 30, with higher scores indicating greater symptom severity. We utilized a cutoff score of ≥ 13 to identify women with probable major depression and ≥ 10 to identify possible depression, based on validation studies in similar populations. The EPDS has good internal consistency (Cronbach’s α = 0.87) and test-retest reliability in perinatal women. The Generalized Anxiety Disorder-7 (GAD-7) scale was employed as the primary anxiety assessment tool. This 7-item instrument measures symptoms of generalized anxiety disorder over the past two weeks, with items rated on a 4-point scale (0-3, from “not at all” to “nearly every day”). Total scores range from 0 to 21, with cutoff scores of ≥ 10 indicating moderate anxiety and ≥ 15 indicating severe anxiety. The GAD-7 has demonstrated excellent internal consistency (Cronbach’s α = 0.92) and good criterion validity for identifying anxiety disorders. While originally developed for the general population, recent studies have validated its use in perinatal women, showing superior specificity compared to anxiety subscales of other screening tools, such as the State-Trait Anxiety Inventory (STAI), which provides complementary assessment of anxiety, distinguishing between state anxiety (temporary, situational feelings) and trait anxiety (stable, enduring characteristics). The STAI State subscale consists of 20 items that measure current anxiety symptoms, whereas the STAI Trait subscale contains 20 items that assess general anxiety proneness. Items are rated on 4-point scales, with total scores for each subscale ranging from 20 to 80. Higher scores indicated greater anxiety levels. We used established cutoffs of ≥ 40 for significant state anxiety and trait anxiety. Although some items may have been confounded by normal pregnancy symptoms, we administered the Pregnancy-Related Anxiety Questionnaire-Revised, a brief measure assessing concerns specific to pregnancy, childbirth, and infant well-being, to perinatal populations. This instrument helps distinguish pregnancy-specific concerns from general anxiety symptoms and is particularly relevant for women experiencing high-risk pregnancies, such as those with preeclampsia.

Clinical and demographic data

Comprehensive demographic information was collected at enrollment through structured interviews and medical record reviews. The data included maternal age, race/ethnicity, educational level, employment status, marital status, household income, parity, gravidity, body mass index at conception and enrollment, smoking status, and relevant medical and obstetric histories. We specifically documented history of previous preeclampsia, chronic medical conditions, previous psychiatric diagnoses or treatment, family history of preeclampsia and mental health disorders, and pregnancy intention. Detailed clinical data were collected throughout the study period, including blood pressure measurements at each visit (recorded as both systolic and diastolic values), 24-hour urine protein quantification or spot protein/creatinine ratios, laboratory parameters including complete blood count with platelet count, comprehensive metabolic panel with liver function tests, serum creatinine, and uric acid levels. Disease severity was classified according to American College of Obstetricians and Gynecologists criteria as preeclampsia with or without severe features, with severe features defined by systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 110 mmHg, thrombocytopenia, elevated liver enzymes, renal insufficiency, pulmonary edema, or cerebral or visual symptoms. Pregnancy outcome data were systematically recorded, including gestational age at delivery, mode of delivery (vaginal or cesarean), birthweight, Apgar scores, neonatal intensive care unit (NICU) admission, presence of fetal growth restriction (defined as birthweight < 10% for gestational age), preterm delivery (< 37 weeks), and maternal complications including eclampsia, Hemolysis, elevated liver enzymes and Low Platelets syndrome, placental abruption, and need for antihypertensive medications. These outcomes were collected to assess their potential associations with psychological symptoms and characterize the overall disease burden in the study population.

Placental biomarker measurements

Maternal venous blood samples (10 mL) were collected at each visit, following standardized phlebotomy protocols. When possible, samples were obtained after at least 4 hours of fasting, collected in serum separator tubes, and allowed to clot at room temperature for 30 minutes. Samples were then centrifuged at 3000 rpm for 15 minutes at 4 °C, and serum was aliquoted into cryovials and immediately frozen at -80 °C until batch analysis. Serum concentrations of sFlt-1 and PlGF were measured using commercially available electrochemiluminescence immunoassays (Roche Diagnostics, Elecsys sFlt-1 and PlGF assays) performed on an automated analyzer. These assays have been extensively validated and are Food and Drug Administration-approved for clinical use in preeclampsia assessment. The sFlt-1 assay has a measuring range of 10-85000 pg/mL with intra-assay and inter-assay coefficients of variation of < 3% and < 5%, respectively. The PlGF assay measures concentrations from 3 pg/mL to 10000 pg/mL with similar precision. Quality control samples at low, medium, and high concentrations were included in each analytical run to ensure assay performance. The sFlt-1/PlGF ratio was calculated by dividing the sFlt-1 concentration by the PlGF concentration for each sample. This ratio demonstrated superior diagnostic and prognostic performance compared to individual markers. Values < 38 are generally considered to rule out preeclampsia in the next 1-4 weeks, values > 38 indicate an increased risk, and values > 85 suggest a high likelihood of preeclampsia requiring delivery within a short timeframe. We analyzed both the absolute concentrations of individual biomarkers and the sFlt-1/PlGF ratio in relation to psychological symptoms. Additional angiogenic biomarkers, including soluble endoglin, were measured in a subset of samples to provide a more comprehensive assessment of the anti-angiogenic state. Samples were analyzed using enzyme-linked immunosorbent assay kits following the manufacturer’s protocols. All biomarker measurements were performed in duplicate, and the mean values were used for analysis.

Neuroendocrine assessments

Salivary cortisol sampling is a non-invasive method for assessing HPA axis function. Participants collected saliva samples at home using saliva collection devices at four time points throughout the day: Immediately upon awakening (before getting out of bed), 30 minutes after awakening to capture the cortisol awakening response (CAR), in the late afternoon (4:00-5:00 PM), and before bedtime (9:00-10:00 PM). Detailed written and verbal instructions were provided to ensure proper collection technique. Participants were instructed to avoid eating, drinking (except water), smoking, or brushing teeth for 30 minutes prior to each sample collection, which were collected on the same day as the study visits when possible, or within 1 week of the visit. To monitor compliance, participants were provided with time-stamped collection logs and received electronic reminders via smartphone applications 5 minutes before each scheduled collection time. The participants recorded the exact collection times and any deviations from the protocol. The compliance rate was 94.3%, with samples showing collection time deviations > 15 minutes from the protocol flagged as potential outliers. Sensitivity analyses excluding these samples (n = 12) showed no significant changes in cortisol-psychological symptom associations. Salivettes were stored in participants’ home freezers until the next study visit, when they were transported to the laboratory on ice and stored at -20 °C until analysis. Salivary cortisol concentrations were determined using a high-sensitivity enzyme immunoassay with a detection range of 0.5-80 nmol/L. Intra-assay and inter-assay coefficients of variation were < 5% and < 8%, respectively. We calculated several cortisol metrics for analysis: (1) Morning cortisol level (awakening sample); (2) CAR (defined as the increase from awakening to 30-minute post-awakening sample); (3) Diurnal slope (calculated as the decline from morning to evening cortisol); and (4) Area under the curve (AUC) with respect to ground, representing total cortisol output across the day. These metrics provide complementary information about the different aspects of the HPA axis function and circadian rhythm regulation.

Statistical analysis

Statistical analyses were performed using SPSS version 27.0 and R statistical software version 4.2.0. All tests were two-tailed, with statistical significance set at P < 0.05. Missing data were handled using multiple imputation methods when appropriate and sensitivity analyses were conducted to assess the impact of missing data on the results.

Descriptive statistics included means with standard deviations for continuous variables, and frequencies with percentages for categorical variables. Normality of distributions was assessed using Shapiro-Wilk tests and Q-Q plots. Variables with skewed distributions were transformed (log transformation) or analyzed using nonparametric methods, as appropriate.

Baseline characteristics were compared between the preeclampsia and control groups using independent sample t-tests for continuous variables with normal distributions, Mann-Whitney U tests for non-normally distributed continuous variables, and χ² tests or Fisher’s exact tests for categorical variables. The effect sizes were calculated using Cohen’s d for continuous variables and odds ratios for categorical variables.

Psychological symptom scores (EPDS, GAD-7, STAI-State, and STAI-Trait) were compared between groups using independent sample t-tests or Mann-Whitney U tests, as appropriate. Repeated-measures analysis of variance or mixed-effects models were employed to assess changes in psychological symptoms over time (enrollment, third trimester, and postpartum) and to test for group-by-time interactions. Post hoc pairwise comparisons with Bonferroni correction were conducted when significant main effects or interactions were detected.

Pearson or Spearman correlation coefficients were calculated to examine the bivariate associations between placental biomarkers (sFlt-1, PlGF, and the sFlt-1/PlGF ratio), cortisol metrics, and psychological symptom scores. Correlation matrices were constructed to identify the patterns of associations. Fisher’s r-to-Z transformation was used to compare the correlation coefficients between groups.

Multivariable linear regression models were constructed to identify independent predictors of psychological symptom scores. Separate models were built with the EPDS, GAD-7, and STAI-State scores as dependent variables. The predictive variables included demographic factors (age, education, and parity), clinical factors (disease severity, gestational age at diagnosis, and pregnancy complications), placental biomarkers (sFlt-1/PlGF ratio), and neuroendocrine measures (morning cortisol, CAR, and diurnal slope). Multicollinearity was assessed using variance inflation factors, with a variance inflation factor > 5 indicating problematic collinearity. Regression diagnostics, including residual plots and influence statistics, were examined to verify model assumptions and identify outliers.

Logistic regression was used to identify predictors of clinically significant depression (EPDS ≥ 13) and anxiety (GAD-7 ≥ 10). Receiver operating characteristic curves were constructed to assess the discriminative ability of placental biomarkers and cortisol measures for predicting psychological disorders, with AUC calculated as a measure of overall predictive performance. Subgroup analyses were conducted comparing early-onset vs late-onset preeclampsia, preeclampsia with vs without severe features, and preeclampsia with vs without adverse pregnancy outcomes. These analyses explored whether specific disease phenotypes were associated with different psychological symptom burdens. Mediation analyses using bootstrapping procedures (5000 bootstrap samples) were performed to assess whether placental biomarkers or neuroendocrine measures mediated the relationship between preeclampsia and psychological symptoms. Path analysis tested the direct and indirect effects by calculating 95% bias-corrected confidence intervals (CIs). Sample size calculations were based on detecting a medium effect size (Cohen’s d = 0.5) for differences in EPDS scores between groups with 80% power and α = 0.05, indicating a required sample size of approximately 100 participants per group. This sample size also provided adequate power (> 80%) for detecting correlations of r ≥ 0.25 and for multivariable regression models with up to 10 predictor variables.

RESULTS

Participant characteristics

A total of 210 women completed the study, 105 in the preeclampsia group and 105 in the control group. The demographic and clinical characteristics of the study population are summarized in Table 1. The groups were well matched for maternal age, gestational age at enrollment, and most sociodemographic factors. Women in the preeclampsia group had significantly higher pre-pregnancy body mass index (mean 28.4 ± 5.8 kg/m² vs 24.2 ± 4.1 kg/m², P < 0.001) and were more likely to be nulliparous (68.6% vs 51.4%, P = 0.012) compared to controls. There were no significant differences between groups in terms of educational level, marital status, or ethnicity.

Table 1 Baseline demographic and clinical characteristics, n (%)/mean ± SD.

Characteristic	Preeclampsia (n = 105)	Control (n = 105)	P value
Maternal age (years)	31.2 ± 5.4	30.5 ± 4.8	0.318
Gestational age at enrollment (weeks)	32.8 ± 3.6	32.4 ± 2.9	0.372
Pre-pregnancy body mass index (kg/m2)	28.4 ± 5.8	24.2 ± 4.1	< 0.001
Nulliparity	72 (68.6)	54 (51.4)	0.012
Race/ethnicity			0.445
White	63 (60.0)	67 (63.8)
Black	18 (17.1)	15 (14.3)
Hispanic	16 (15.2)	14 (13.3)
Asian	8 (7.6)	9 (8.6)
Education level			0.528
High school or less	22 (21.0)	19 (18.1)
Some college	35 (33.3)	32 (30.5)
College graduate	48 (45.7)	54 (51.4)
Married/partnered	89 (84.8)	91 (86.7)	0.694
Employed	76 (72.4)	81 (77.1)	0.437
Smoking during pregnancy	8 (7.6)	6 (5.7)	0.574

The clinical characteristics of the preeclampsia group showed that 26.7% had early onset disease (< 34 weeks) and 61.9% met the criteria for severe features. Mean systolic and diastolic blood pressures at diagnosis were 158.3 ± 14.2 mmHg and 102.4 ± 10.8 mmHg, respectively. Proteinuria was documented in 89.5% of cases, with a mean 24-hour urine protein of 2.8 ± 2.1 g.

Pregnancy outcomes

The pregnancy outcomes differed significantly between the groups (Table 2). Women with preeclampsia delivered earlier (mean gestational age 36.2 ± 2.8 weeks vs 39.1 ± 1.2 weeks, P < 0.001), had higher rates of cesarean delivery (64.8% vs 28.6%, P < 0.001), and were more likely to experience preterm birth (51.4% vs 4.8%, P < 0.001). Infants born to mothers with preeclampsia had lower birth weights (mean 2548 ± 624 g vs 3298 ± 412 g, P < 0.001) and higher rates of fetal growth restriction (28.6% vs 5.7%, P < 0.001). NICU admission was required in 45.7% and 8.6% of infants in the preeclampsia and control groups, respectively (P < 0.001).

Table 2 Pregnancy and neonatal outcomes, n (%)/mean ± SD.

Outcome	Preeclampsia (n = 105)	Control (n = 105)	P value
Gestational age at delivery (weeks)	36.2 ± 2.8	39.1 ± 1.2	< 0.001
Preterm delivery < 37 weeks	54 (51.4)	5 (4.8)	< 0.001
Cesarean delivery	68 (64.8)	30 (28.6)	< 0.001
Birthweight (g)	2548 ± 624	3298 ± 412	< 0.001
Birthweight < 10%	30 (28.6)	6 (5.7)	< 0.001
5-minute Apgar < 7	12 (11.4)	2 (1.9)	0.004
Neonatal intensive care unit admission	48 (45.7)	9 (8.6)	< 0.001
Maternal complications
Hemolysis, elevated liver enzymes and low platelet syndrome	15 (14.3)	0 (0)	< 0.001
Eclampsia	3 (2.9)	0 (0)	0.246
Placental abruption	8 (7.6)	1 (1.0)	0.035

Psychological symptom scores

Women with preeclampsia demonstrated significantly higher depression and anxiety symptom scores across all time points and measures than normotensive controls (Table 3). At enrollment, mean EPDS scores were 12.8 ± 5.4 in the preeclampsia group vs 6.2 ± 3.1 in controls (P < 0.001, Cohen’s d = 1.52). This difference persisted at the third trimester assessment (13.4 ± 5.8 vs 6.8 ± 3.4, P < 0.001) and at 6 weeks postpartum (11.7 ± 5.5 vs 6.4 ± 3.2, P < 0.001).

Table 3 Psychological symptom scores by group and time point, mean ± SD.

Measure	Time point	Preeclampsia (n = 105)	Control (n = 105)	P value	Effect size (d)
Edinburgh Postnatal Depression Scale	Enrollment	12.8 ± 5.4	6.2 ± 3.1	< 0.001	1.52
	Third trimester	13.4 ± 5.8	6.8 ± 3.4	< 0.001	1.42
	Postpartum	11.7 ± 5.5	6.4 ± 3.2	< 0.001	1.19
Generalized Anxiety Disorder-7	Enrollment	10.3 ± 4.2	5.1 ± 2.8	< 0.001	1.48
	Third trimester	11.1 ± 4.6	5.4 ± 3.0	< 0.001	1.51
	Postpartum	9.2 ± 4.3	5.2 ± 2.9	< 0.001	1.09
STAI-State	Enrollment	44.6 ± 9.8	32.4 ± 7.2	< 0.001	1.42
	Third trimester	46.2 ± 10.4	33.1 ± 7.8	< 0.001	1.45
	Postpartum	41.8 ± 9.6	31.9 ± 7.4	< 0.001	1.16
STAI-Trait	Enrollment	42.5 ± 10.5	34.8 ± 8.2	< 0.001	0.82
	Third trimester	43.1 ± 10.8	35.2 ± 8.6	< 0.001	0.81
	Postpartum	39.2 ± 9.8	34.5 ± 8.4	< 0.001	0.52

STAI: State-Trait Anxiety Inventory.

GAD-7 scores showed similar patterns, with preeclampsia-associated elevations at enrollment (10.3 ± 4.2 vs 5.1 ± 2.8, P < 0.001), third trimester (11.1 ± 4.6 vs 5.4 ± 3.0, P < 0.001), and postpartum (9.2 ± 4.3 vs 5.2 ± 2.9, P < 0.001). STAI-State scores were consistently elevated in women with preeclampsia (enrollment: 44.6 ± 9.8 vs 32.4 ± 7.2, P < 0.001; third trimester: 46.2 ± 10.4 vs 33.1 ± 7.8, P < 0.001; postpartum: 41.8 ± 9.6 vs 31.9 ± 7.4, P < 0.001).

The prevalence of clinically significant symptoms was significantly higher in the preeclampsia group. At enrollment, 65 women with preeclampsia (61.9%) scored ≥ 10 on the EPDS (indicating possible depression) compared to 19 controls (18.1%), P < 0.001. Using the more stringent cutoff of ≥ 13 for probable major depression, 42 women with preeclampsia (40.0%) vs 8 controls (7.6%) met criteria (P < 0.001). For anxiety, 58 women with preeclampsia (55.2%) scored ≥ 10 on the GAD-7 (moderate to severe anxiety) compared to 15 controls (14.3%), P < 0.001.

Repeated-measures analysis revealed a significant group-by-time interaction for EPDS scores (F = 3.89, P = 0.021), indicating that the trajectory of depressive symptoms differed between the groups. While both groups showed slight increases from enrollment to the third trimester, followed by modest decreases postpartum, the magnitude of change was greater in the preeclampsia group.

Placental biomarkers

Placental biomarker concentrations differed dramatically between the groups, confirming the presence of severe placental dysfunction in the preeclampsia cohort (Table 4). Women with preeclampsia had markedly elevated sFlt-1 levels [median 8245 pg/mL, interquartile range (IQR) 4532-14876 vs median 1876 pg/mL, IQR 1234-2654 in controls, P < 0.001] and substantially reduced PlGF concentrations (median 42 pg/mL, IQR 24-78 vs median 284 pg/mL, IQR 198-412 in controls, P < 0.001). The sFlt-1/PlGF ratio was dramatically elevated in preeclampsia (median 186, IQR 94-342 vs median 7.2, IQR 4.8-11.4 in controls, P < 0.001).

Table 4 Placental biomarker concentrations at enrollment, median (interquartile range).

Biomarker	Preeclampsia (n = 105)	Control (n = 105)	P value
The sFlt-1 (pg/mL)	8245 (4532-14876)	1876 (1234-2654)	< 0.001
PlGF (pg/mL)	42 (24-78)	284 (198-412)	< 0.001
The sFlt-1/PlGF ratio	186 (94-342)	7.2 (4.8-11.4)	< 0.001
Soluble endoglin (ng/mL)	48.6 (32.4-72.8)	12.4 (8.6-18.2)	< 0.001

P value from Mann-Whitney U test. sFIt: Soluble fms-like tyrosine kinase-1; PlGF: Placental growth factor.

In the preeclampsia group, women with early onset disease had higher sFlt-1 levels (median 12654 pg/mL vs 6832 pg/mL in the late-onset group, P = 0.003) and lower PlGF levels (median 28 pg/mL vs 54 pg/mL, P = 0.008), resulting in higher sFlt-1/PlGF ratios (median 284 vs 148, P = 0.001).

Associations between placental biomarkers and psychological symptoms

Correlation analyses revealed significant associations between placental biomarkers and the severity of psychological symptoms. The sFlt-1/PlGF ratio correlated positively with EPDS (r = 0.42, P < 0.001), GAD-7 (r = 0.38, P < 0.001), and STAI-State scores (r = 0.36, P < 0.001) at enrollment. These correlations remained significant in the preeclampsia group (EPDS: r = 0.35, P < 0.001; GAD-7: r = 0.31, P = 0.001; STAI-State: r = 0.28, P = 0.004).

The sFlt-1 concentrations showed positive correlations with depression and anxiety scores (EPDS: r = 0.38, P < 0.001; GAD-7: r = 0.34, P < 0.001), while PlGF levels demonstrated inverse correlations (EPDS: r = -0.32, P < 0.001; GAD-7: r = -0.29,P = 0.001). Soluble endoglin also correlated with psychological symptoms, although the correlations were slightly weaker than those observed for the sFlt-1/PlGF ratio.

Women with sFlt-1/PlGF ratios > 85 (n = 72 in preeclampsia group) had significantly higher EPDS scores compared to those with ratios ≤ 85 (14.2 ± 5.2 vs 10.1 ± 4.8, P < 0.001) and GAD-7 scores (11.4 ± 4.3 vs 8.2 ± 3.8, P < 0.001). This threshold has clinical significance, as it indicates a high likelihood of adverse outcomes and the need for delivery.

Neuroendocrine findings

Salivary cortisol profiles differed between the groups, with women with preeclampsia showing evidence of HPA axis dysregulation (Table 5). Morning awakening cortisol levels were elevated in the preeclampsia group (mean 16.8 ± 4.2 nmol/L vs 14.1 ± 3.4 nmol/L in controls, P < 0.001). The CAR was blunted in women with preeclampsia (mean increase 3.2 ± 2.4 nmol/L vs 5.1 ± 2.8 nmol/L in controls, P < 0.001), indicating impaired stress responsiveness.

Table 5 Salivary cortisol measures at enrollment, mean ± SD.

Measure	Preeclampsia (n = 105)	Control (n = 105)	P value
Morning cortisol (nmol/L)	16.8 ± 4.2	14.1 ± 3.4	< 0.001
Cortisol awakening response (nmol/L)	3.2 ± 2.4	5.1 ± 2.8	< 0.001
Evening cortisol (nmol/L)	5.8 ± 2.1	4.2 ± 1.6	< 0.001
Diurnal slope (nmol/L/hour)	-0.68 ± 0.32	-0.82 ± 0.28	0.002
Area under the curve with respect to ground (nmol/L/hour)	198.4 ± 52.6	176.2 ± 41.8	0.001

Cortisol awakening response calculated as 30-minute post-awakening minus the awakening value. Area under the curve with respect to ground representing the total daily cortisol output.

Evening cortisol levels remained elevated in preeclampsia (5.8 ± 2.1 nmol/L vs 4.2 ± 1.6 nmol/L, P < 0.001), and the diurnal slope was flattened (-0.68 ± 0.32 nmol/L/hour vs -0.82 ± 0.28 nmol/L/hour, P = 0.002), indicating disrupted circadian rhythm. Total daily cortisol output (AUC with respect to ground) was higher in women with preeclampsia (198.4 ± 52.6 nmol/L/hour vs 176.2 ± 41.8 nmol/L/hour, P = 0.001).

Within the preeclampsia group, women who met criteria for probable major depression (EPDS ≥ 13) had significantly higher morning cortisol levels compared to those without depression (18.7 ± 4.3 nmol/L vs 14.2 ± 3.1 nmol/L, P = 0.002) and more severely blunted CAR (2.4 ± 1.8 nmol/L vs 4.2 ± 2.6 nmol/L, P = 0.003). Similar patterns were observed for anxiety, with women scoring GAD-7 ≥ 10 showing higher morning cortisol (17.9 ± 4.5 nmol/L vs 14.8 ± 3.2 nmol/L, P = 0.006).

Correlation analyses revealed that morning cortisol levels were positively correlated with the EPDS (r = 0.34, P < 0.001), GAD-7 (r = 0.29, P = 0.002), and STAI-State scores (r = 0.31, P = 0.001) in the preeclampsia group. The magnitude of CAR blunting (smaller increase) was associated with higher depression scores (r = -0.28, P = 0.004). Flattened diurnal slopes correlated with elevated anxiety symptoms (r = 0.26, P = 0.008).

Predictors of psychological symptoms

Multivariate linear regression models identified several independent predictors of depressive and anxiety symptoms (Table 6). For EPDS scores, significant predictors included sFlt-1/PlGF ratio (β = 0.28, P = 0.003), morning cortisol level (β = 0.31, P = 0.001), disease severity (presence of severe features, β = 0.35, P < 0.001), nulliparity (β = 0.22, P = 0.015), and adverse pregnancy outcomes (β = 0.24, P = 0.008). The overall model explained 52.4% of the variance in EPDS scores (adjusted R² = 0.524, F = 18.34, P < 0.001).

Table 6 Multivariable regression models for psychological symptom scores, β (95%CI).

Predictor	Edinburgh Postnatal Depression Scale score	Generalized Anxiety Disorder-7 score	State-Trait Anxiety Inventory-State score
Soluble fms-like tyrosine kinase-1/placental growth factor ratio (per 100 units)	0.28 (0.12-0.44)b	0.25 (0.09-0.41)b	0.23 (0.08-0.38)b
Morning cortisol (nmol/L)	0.31 (0.16-0.46)c	0.27 (0.12-0.42)b	0.29 (0.14-0.44)c
Severe features (yes vs no)	0.35 (0.19-0.51)c	0.32 (0.16-0.48)c	0.30 (0.14-0.46)c
Early-onset preeclampsia (yes vs no)	0.18 (0.02-0.34)a	0.16 (-0.01 to 0.33)	0.14 (-0.03 to 0.31)
Nulliparity (yes vs no)	0.22 (0.06-0.38)a	0.19 (0.03-0.35)a	0.17 (0.01-0.33)a
Adverse outcomes (yes vs no)	0.24 (0.08-0.40)b	0.21 (0.05-0.37)a	0.20 (0.04-0.36)a
Pre-pregnancy body mass index (kg/m2)	0.12 (-0.04 to 0.28)	0.10 (-0.06 to 0.26)	0.09 (-0.07 to 0.25)
Model R2 (adjusted)	0.524	0.478	0.441

^aP < 0.05.

^bP < 0.01.

^cP < 0.001.

Adverse outcomes were defined as a composite of preterm birth, fetal growth restriction, or neonatal intensive care unit admission. Models adjusted for maternal age, education, and gestational age at enrollment.

For GAD-7 scores, independent predictors were sFlt-1/PlGF ratio (β = 0.25, P = 0.008), morning cortisol (β = 0.27, P = 0.003), disease severity (β = 0.32, P < 0.001), nulliparity (β = 0.19, P = 0.032), and adverse outcomes (β = 0.21, P = 0.018). This model explained 47.8% of the variance (adjusted R² = 0.478, F = 15.82, P < 0.001).

Similar patterns emerged for STAI-State scores, with sFlt-1/PlGF ratio (β = 0.23, P = 0.012), morning cortisol (β = 0.29, P = 0.002), disease severity (β = 0.30, P < 0.001), nulliparity (β = 0.17, P = 0.044), and adverse outcomes (β = 0.20, P = 0.026) serving as independent predictors (adjusted R² = 0.441, F = 14.26, P < 0.001).

Logistic regression models predicting clinically significant depression (EPDS ≥ 13) revealed that women with sFlt-1/PlGF ratio > 85 had 3.8-fold increased odds (95%CI: 1.8-8.2, P < 0.001) of meeting depression criteria compared to those with lower ratios. Morning cortisol > 18 nmol/L was associated with 2.9-fold increased odds (95%CI: 1.4-6.1, P = 0.004) of depression. Presence of severe features conferred 4.2-fold increased odds (95%CI: 2.0-8.9, P < 0.001).

Receiver operating characteristic curve analysis demonstrated that a composite predictor combining sFlt-1/PlGF ratio, morning cortisol, and disease severity achieved an AUC of 0.81 (95%CI: 0.74-0.88) for predicting depression and 0.78 (95%CI: 0.71-0.85) for predicting anxiety, indicating good discriminative ability.

Subgroup analyses

A comparison of early-and late-onset preeclampsia revealed that women with early onset disease had higher psychological symptom scores across all measures. The mean EPDS scores were 15.2 ± 5.6 in the early-onset vs 11.8 ± 5.1 and late-onset preeclampsia (P = 0.008). GAD-7 scores were similarly elevated (12.4 ± 4.5 vs 9.4 ± 3.9, P = 0.002). These differences persisted even after adjusting for disease severity and pregnancy outcomes.

Women with preeclampsia and severe features had a higher symptom burden than those without severe features. EPDS scores were 13.9 ± 5.4 vs 10.2 ± 4.8 (P < 0.001), and GAD-7 scores were 11.6 ± 4.4 vs 8.1 ± 3.6 (P < 0.001). Adverse pregnancy outcomes (preterm birth, fetal growth restriction, or NICU admission) were associated with elevated symptoms regardless of disease severity.

Stratification by psychological symptom severity revealed a dose-response relationship with biological markers. Women with severe depression (EPDS ≥ 19) had sFlt-1/PlGF ratios that were 1.6-fold higher than those with mild-moderate depression (EPDS 10-18), who in turn had ratios 2.1-fold higher than those without depression (EPDS < 10), P < 0.001.

DISCUSSION

This prospective study provides comprehensive evidence that women with preeclampsia experience substantially elevated rates of anxiety and depressive symptoms throughout the perinatal period compared with normotensive pregnant women. Our findings demonstrated that more than 60% of women with preeclampsia met the screening criteria for clinically significant anxiety or depression, representing a three-fold increase compared to healthy controls. Beyond documenting this elevated prevalence, our study uniquely identified the biological correlates of the psychological symptom burden, revealing significant associations between placental dysfunction biomarkers, neuroendocrine dysregulation, and mental health outcomes. These findings have important implications for understanding the pathophysiology linking preeclampsia to perinatal mental health disorders, and for developing targeted screening and intervention strategies.

The magnitude of the psychological symptom burden we observed in women with preeclampsia aligns with and extends recent literature. A 2025 study examining anxiety and depression in women admitted for severe preeclampsia reported STAI-State scores of 27 (moderate severity) and elevated EPDS scores compared to women with uncomplicated pregnancies[16]. Our findings of mean STAI-State scores exceeding 44 and EPDS scores of 12.8 in women with preeclampsia, suggest an even greater symptom burden, possibly reflecting our inclusion of both early onset and late-onset disease and comprehensive follow-up throughout the postpartum period. Similarly, recent cross-sectional research has demonstrated higher pregnancy stress, anxiety, and depression in women at a high risk of preeclampsia[17], though most prior studies have been limited by cross-sectional designs that cannot establish temporal relationships or examine biological mechanisms.

The temporal trajectory of observed psychological symptoms provides important insights into disease progression and recovery. While anxiety and depression scores were elevated at all time points in women with preeclampsia, we noted a slight increase from enrollment to the third trimester, followed by a modest postpartum improvement. This pattern suggests that the acute stress of active disease and associated complications may exacerbate symptoms, whereas delivery, the definitive treatment for preeclampsia, offers some relief. However, the persistence of elevated symptoms at six weeks postpartum, with mean EPDS scores remaining nearly double those of the controls, indicates that the psychological impact of preeclampsia extends beyond pregnancy resolution. This finding emphasizes the need for continued mental health screening and support during the postpartum period in women with a history of preeclampsia[18].

Our examination of placental biomarkers represents one of the first attempts to link objective measures of placental dysfunction with the severity of psychological symptoms in preeclampsia. The significant positive correlation between the sFlt-1/PlGF ratio and depression and anxiety scores suggests that the degree of placental pathology directly influences maternal psychological wellbeing. The sFlt-1/PlGF ratio reflects the antiangiogenic state underlying preeclampsia, with elevated ratios indicating severe placental ischemia and dysfunction[19,20]. Our finding that women with ratios > 85 had nearly four-fold increased odds of meeting the criteria for major depression provides a potential biological marker for identifying those at the highest risk of mental health complications.

Several mechanisms can explain the association between placental biomarkers and psychological symptoms. First, elevated sFlt-1 levels induce widespread endothelial dysfunction, affecting not only the placental vasculature but also the cerebral blood vessels[21]. Emerging evidence suggests that vascular inflammation and endothelial dysfunction play roles in the pathophysiology[22]. Notably, the sFlt-1/PlGF ratio reflects placental ischemia and systemic endothelial dysfunction, and it is plausible that these factors may affect intracranial inflammation or neurovascular unit integrity through blood-brain barrier disruption, thereby participating in emotion regulation; however, our current correlational analysis cannot establish causality, and future studies employing mediation models or pathway analysis are needed to further explore the causal pathway of “placenta-endocrine-psychological symptoms”. Second, the systemic inflammatory state characteristic of severe preeclampsia, reflected in part by biomarker elevations, may directly affect neurotransmitter systems and brain function. Third, awareness of disease severity (conveyed through biomarker results or clinical communications) may contribute to psychological distress via psychological pathways. However, the correlations that we observed persisted even when controlling for clinically communicated disease severity, suggesting a biological rather than a purely psychological mediation.

Our neuroendocrine findings provide additional mechanistic insights. Elevated morning cortisol levels and flattened diurnal rhythms observed in women with preeclampsia are consistent with HPA axis dysregulation. Importantly, these abnormalities were most pronounced in women who met the criteria for depression, with morning cortisol levels significantly higher in depressed women than in non-depressed women with preeclampsia. The blunted CAR we documented is particularly notable, as this pattern has been associated with chronic stress exposure and depression in non-pregnant populations[23]. Whether HPA axis changes precede or follow the development of depression in preeclampsia remains uncertain, although our longitudinal data showing associations between early cortisol measures and subsequent symptom trajectories suggest that neuroendocrine dysregulation may contribute to mental health risks.

However, the relationship between cortisol levels and preeclampsia remains unclear. While some studies have proposed that psychological stress and elevated cortisol levels contribute to the development of preeclampsia through hypertension and endothelial dysfunction[24], others have found no evidence that cortisol or anxiety predicts subsequent preeclampsia[25]. Our data support a model wherein preeclampsia induces both placental dysfunction and alterations in the HPA axis, which together contribute to psychological symptom burden, as evidenced by the dose-response relationships between biomarker abnormalities and symptom severity. Disease severity has emerged as the strongest predictor of psychological symptoms, reflecting greater health risks and the need for intensive intervention. The association of nulliparity with elevated symptoms likely reflects inexperience and reproductive concerns, whereas adverse pregnancy outcomes underscore the additional stress from fetal complications. Early onset preeclampsia showed higher symptom burdens than late-onset preeclampsia, consistent with more severe placental pathology and higher sFlt-1/PlGF ratios[26], suggesting the need for intensive mental health screening in women diagnosed remotely at term. These findings support routine mental health screening in preeclampsia populations[27], with the sFlt-1/PlGF ratio and morning cortisol levels potentially serving as risk markers pending further validation. Based on our findings, we propose that pregnant women with an sFlt-1/PlGF ratio > 85 should be flagged for routine psychological follow-up, given the nearly four-fold increased odds of depression observed at this threshold. Future research should explore whether a simple composite risk score incorporating the sFlt-1/PlGF ratio and morning cortisol level can be developed and validated for screening pregnant women at high risk of psychological distress. Symptom persistence through 6 weeks postpartum indicates the need for extended screening beyond hospital discharge.

Our results must be interpreted within the context of the limitations of this study. First, although our sample size was adequate for the primary analyses, the statistical power for some subgroup comparisons was limited. Second, we assessed psychological symptoms using validated screening tools rather than structured diagnostic interviews, which may have resulted in some misclassification of clinical disorders. Therefore, the proportion of “clinically significant symptoms” reported here reflects screening positivity rather than confirmed clinical diagnoses, and future studies should incorporate structured clinical interviews as the diagnostic gold standard. However, the instruments we employed are widely used in perinatal research and clinical practice, and have demonstrated good psychometric properties. Third, our cortisol sampling protocol relied on at-home collections, which introduces potential compliance and timing variability despite our detailed instructions. Participants were provided with time-stamped collection logs and electronic reminders via smartphone applications, and samples with reported collection times deviating more than 15 minutes from the protocol were flagged for sensitivity analysis, with no significant differences observed when excluding these outliers. Fourth, we measured biomarkers at limited time points rather than throughout pregnancy, which may have overlooked dynamic changes in biological processes. Fifth, our study population was drawn from a single tertiary maternal and child health hospital, which, while helping to control for medical environmental variables, may limit generalizability to populations with different medical resources, cultural backgrounds, or psychological coping styles; future multi-center studies across diverse populations are warranted to validate these findings.

CONCLUSION

This study demonstrated that preeclampsia is associated with substantially elevated rates of anxiety and depressive symptoms throughout the perinatal period. The significant correlations identified among placental dysfunction biomarkers, neuroendocrine dysregulation, and psychological symptom severity suggest potential biological pathways linking pregnancy complications to mental health outcomes.