Anxiety and hypertensive disorders of pregnancy: Epidemiology, mechanisms, and management strategies

Abstract

This article comprehensively explores the relationship between anxiety and hypertensive disorders of pregnancy (HDP), covering epidemiology, potential mechanisms, and management strategies. HDP is the second leading cause of maternal and perinatal morbidity and mortality, encompassing subtypes such as gestational hypertension, preeclampsia, and eclampsia. Research indicates that anxiety is closely associated with the occurrence of HDP, potentially influencing blood pressure regulation and vascular function through neuroendocrine, inflammatory, genetic, and gut microbiota effects. Epidemiological data show that anxiety is prevalent during pregnancy and is linked to an increased risk of HDP. Biological mechanism studies reveal that anxiety can increase the risk of HDP by activating the hypothalamic-pituitary-adrenal axis, promoting inflammation, and affecting gut microbiota. In terms of treatment and management, psychological interventions (such as relaxation training, yoga, and mindfulness meditation) and pharmacological treatments (such as labetalol and nifedipine) play important roles in alleviating anxiety and improving the prognosis of HDP. Additionally, multidisciplinary collaboration and long-term postpartum follow-up are crucial for reducing the long-term risk of cardiovascular diseases. Despite significant progress in research on anxiety and HDP, many issues still require further exploration, including in-depth mechanism studies, optimization of clinical interventions, improvement of multidisciplinary collaboration models, long-term follow-up studies, and the impact of cultural and social factors.

Key Words: Hypertensive disorders of pregnancy; Anxiety; Neuroendocrine Mechanisms; Psychological interventions; Multidisciplinary management

Core Tip: This article examines how anxiety influences hypertensive disorders of pregnancy via neuroendocrine and inflammatory pathways. It highlights the importance of psychological interventions and multidisciplinary care in managing hypertensive disorders of pregnancy, while emphasizing the need for further research on mechanisms, interventions, and long-term outcomes.

INTRODUCTION

Hypertensive disorders of pregnancy (HDP) are the second most common cause of maternal and perinatal morbidity and mortality worldwide. HDP represents a significant global health concern, affecting 5%-10% of pregnancies and contributing to approximately 700000 maternal and 500000 fetal deaths annually. Over the past three decades, advancements in the prevention and management of HDP have led to substantial reduction in the global maternal mortality rate, declining from 39.8 per 100000 in 1990 to 27.8 per 100000 in 2019[1]. These disorders encompass subtypes such as gestational hypertension, preeclampsia, and eclampsia, each significantly associated with adverse maternal and neonatal outcomes[2]. Despite the limited understanding of the pathophysiological mechanisms underlying HDP, recent research suggests that maternal psychological factors may contribute to its development via neuroendocrine, immune, and autonomic nervous system pathways[3].

Among the psychological disorders during pregnancy, anxiety is particularly prevalent, and its association with HDP has drawn increasing scholarly attention. A comprehensive study involving 9 million pregnant women in the United States identified a significant association between anxiety and HDP. The analysis, which used adjusted odds ratios (ORs), demonstrated that anxiety was associated with an increased risk of HDP (OR = 1.324), preeclampsia (OR = 1.522), and eclampsia (OR = 1.813) by 32%, 52%, and 81%, respectively. Conversely, no similar correlation was observed for depression[4]. These findings suggest that anxiety may influence HDP through specific biological pathways, such as the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis or heightened sympathetic activation[5]. Additionally, the use of anxiety-related medication-such as serotonin-norepinephrine reuptake inhibitors (SNRIs)-could potentially increase the risk of HDP by disrupting placental vascular regulation[6].

HDP not only leads to short-term maternal and neonatal complications but is also associated with long-term risks-such as cardiovascular disease, chronic kidney disease, and metabolic syndrome in women[7]. Anxiety, as a chronic stressor, may further amplify these long-term health risks through persistent activation of inflammatory pathways and endothelial dysfunction[8]. This is supported by recent research highlighting the bidirectional relationship between psychological factors and cardiovascular health, where elevated blood pressure has been shown to causally influence neuroticism and anxiety[9]. Studies in immigrant populations have shown that perinatal anxiety rates can reach up to 31% among women from low-income countries, suggesting that sociocultural stressors may exacerbate the risk of HDP by compounding psychological stress[10]. Although international guidelines emphasize physiological monitoring of HDP, a consensus on psychological screening and management remains lacking.

This review systematically examines the epidemiological association between anxiety and HDP, potential mechanisms, and intervention strategies, aiming to provide evidence-based recommendations to optimize perinatal care.

EPIDEMIOLOGY OF ANXIETY AND HDP

HDP are a major contributor to maternal and perinatal morbidity and mortality worldwide. A large-scale study by Raina et al[4], which included 9 million pregnant women, found a significant association between pregnancy-related anxiety and HDP, with the prevalence of anxiety increasing over time. According to the 2023 recommendations of the United States Preventive Services Task Force, HDP accounts for 10%-16% of global maternal deaths, with prevalence rates of 6.3% in the United States and 8.0% in China[11].

Subtypes of HDP, such as gestational hypertension, preeclampsia, and HELLP syndrome, are significantly associated with cardiovascular severe maternal morbidity (cvSMM). A cohort study based on the United States National Inpatient Sample (2015-2019) found that HELLP syndrome had the highest cvSMM risk (adjusted risk ratio [RR], 17.55), followed by severe preeclampsia (RR, 9.11) and chronic hypertension (RR, 3.57). HDP disproportionately affects socially disadvantaged groups, including individuals with lower socioeconomic status, women of color, and older pregnant individuals[12].

Postnatal cardiovascular risk remains a concern for patients with HDP. In this randomized clinical trial involving 220 participants, physician-guided self-management of outpatient postnatal blood pressure, following hypertensive pregnancy, was associated with a 6/5 mmHg lower ambulatory blood pressure at 9 months postpartum[12]. This underscores the importance of both prenatal and postnatal management for long-term health.

The interplay between anxiety and HDP has garnered increasing attention. The prevalence of anxiety during pregnancy varies significantly worldwide, with rates of 13.6% in the United States, 11.23% in Mexico, 55.7% in India, and 16% in China (based on a 2010-2019 meta-analysis); rates are lower in the southern regions (15.3%) than in northern regions (21.3%)[13]. Mechanistic studies suggest that anxiety increases the risk of HDP by activating the sympathetic nervous system and HPA axis, leading to dysregulated blood pressure and endothelial dysfunction[14]. Additionally, anxiety may reduce patient adherence to treatment, further exacerbating disease progression[15].

BIOLOGICAL MECHANISMS LINKING ANXIETY AND HDP

The relationship between anxiety and HDP is complex and involves neuroendocrine, inflammatory, genetic, and epigenetic mechanisms. Multiple studies have demonstrated a close association between pregnancy anxiety and the occurrence of HDP.

Neuroendocrine mechanisms

Both anxiety and HDP are associated with excessive activation of the HPA axis. Chronic stress elevates cortisol levels, which enhance renin-angiotensin system activity, leading to vasoconstriction and elevated blood pressure[16]. Over activation of the sympathetic nervous system further exacerbates anxiety and directly contributes to increased cardiac output and peripheral vascular resistance, thereby elevating blood pressure[17,18].

Inflammatory mechanisms

Inflammation is a key pathophysiological driver of HDP. Luo et al[19] found that miR-210 is significantly upregulated in pre-eclamptic placental tissues, impairing trophoblast invasion and contributing to placental dysfunction. Additionally, proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) can further upregulate microRNA-210, suggesting that an inflammatory microenvironment driven by chronic anxiety can accelerate HDP progression. Furthermore, cytokines such as interleukin-6 (IL-6) and IL-17 can impair vascular endothelial function, promote oxidative stress, and elevate blood pressure[20].

Genetic and epigenetic mechanisms

Mendelian randomization studies suggest a causal relationship between genetic predisposition to HDP and long-term cardiovascular risk. A study by Tschiderer et al[21] found that individuals with high genetic susceptibility to HDP-including non-pregnant women and males-had a significantly increased cardiovascular risk (OR = 1.20-1.38). HDP-associated genetic variants, particularly those regulating blood pressure homeostasis and vascular remodeling (e.g., angiotensinogen gene mutations), can independently contribute to the risk of cardiovascular disease[22].

Gut microbiota and metabolic regulation

Anxiety-related gut microbiota imbalances may influence blood pressure through the "gut-brain-vascular axis". Through the bidirectional communication mechanisms of the gut-brain axis, including the vagus nerve, enteric nervous system, HPA axis, short-chain fatty acids, and neurotransmitter metabolism, the gut microbiota can influence blood pressure regulation. Studies have shown that gut microbiota dysbiosis (such as reduced microbial diversity and decreased beneficial bacteria) is closely related to the occurrence and development of hypertension. Moreover, it is positive to treat anxiety symptoms by regulation of intestinal microbiota[23]. Additionally, psychological states such as anxiety may affect blood pressure by altering the composition of the gut microbiota, which in turn acts through the gut-brain axis[24]. Studies have found that gut microbiota dysbiosis can activate the HPA axis, leading to increased levels of hormones such as corticosterone, which in turn affects blood pressure. This suggests that anxiety-related gut microbiota dysbiosis may influence blood pressure through the neuroendocrine pathways of the gut-brain-vascular axis[25]. Some studies have shown that the gut microbial metabolite trimethylamine-N-oxide (TMAO) induces oxidative stress and promotes vascular smooth muscle proliferation, directly contributing to hypertension[26]. There is currently no fully conclusive evidence that TMAO is a causative factor for atherosclerotic cardiovascular disease. In particular, whether TMAO induces or merely serves as a marker for hypertension and renal dysfunction requires further research[27].

Autonomic nervous system and hemodynamic changes

Anxiety-induced overactivation of the sympathetic nervous system can lead to reduced heart rate variability, increased vascular resistance, and elevated renin release, creating a “vicious cycle” between anxiety and hypertension[28]. Animal models have shown that chronic stress upregulates angiotensin II receptors, further supporting the role of autonomic nervous system dysregulation in blood pressure control[29].

TREATMENT AND MANAGEMENT OF ANXIETY AND HDP

Anxiety and depressive symptoms are closely related to the occurrence of HDP. Moreover, these psychological states may exert their influence through affecting the duration of pregnancy and other adverse pregnancy outcomes[30]. Comprehensive management should follow a biopsychosocial model, integrating psychological interventions, pharmacological regulation, multidisciplinary collaboration, and continuity of care to form a closed-loop management system that can reduce the incidence of severe preeclampsia by 37%[31].

Psychological interventions

Smith et al[32] conducted a systematic review of eight studies to assess the impact of psychological interventions on HDPs. The results showed that relaxation training significantly reduced systolic blood pressure (SBP) [mean difference (MD) -11.3, 95% confidence interval (CI): -13.23 to -9.39] and diastolic blood pressure (DBP) (MD -6.59, 95%CI: -9.43 to -3.75), and alleviated stress (MD -11.4, 95%CI: -16.5 to -6.3). Yoga decreased the risk of gestational hypertension (RR 0.28, 95%CI: 0.09-0.91) and reduced stress. The guided imagery group had lower mean arterial pressure (MD -4.35, 95%CI: -8.04 to -0.66; P = 0.02). Music intervention increased patient satisfaction (MD 11.0, 95%CI: 3.93-19.8) but had no effect on blood pressure. Acupuncture was associated with one case of placental abruption and three adverse events, with no significant differences in blood pressure outcomes compared to controls. Overall, psychological interventions may improve blood pressure control but did not significantly reduce the incidence of preeclampsia (5 studies), antihypertensive drug use (3 studies), or improve neonatal outcomes (5 studies).

Zhang et al[33] studied the effects of cognitive behavioral intervention (CBI) on pregnant women with hypertension. A total of 196 participants were divided into a control group and an observation group (98 in each). The control group received routine care, while the observation group received CBI in addition to routine care. After the intervention, SBP and DBP in the observation group were significantly lower than in the control group (P < 0.05). Specifically, SBP was 127.79 ± 9.24 mmHg vs 139.42 ± 8.63 mmHg, and DBP was 82.53 ± 7.38 mmHg vs 90.78 ± 7.26 mmHg. Additionally, the incidence of postpartum hemorrhage, preeclampsia, cesarean section, placental abruption, neonatal asphyxia, fetal distress, and preterm birth was significantly lower in the observation group (P < 0.05). CBI effectively controlled blood pressure, alleviated negative emotions, improved coping strategies, and enhanced maternal and neonatal outcomes.

Similarly, Sun et al[34] investigated the effects of cognitive-behavioral therapy (CBT) on pregnant women with mild anxiety. The study included 621 participants who were assessed for positive and negative stressors during pregnancy. Results showed that third-trimester stressors, particularly hassles frequency and intensity, were positively associated with postpartum anxiety and depression. The CBT intervention strengthened the positive effects of uplifts and mitigated the negative effects of hassles, demonstrating its efficacy in modulating pregnancy-related stressors.

A study on long-term meditation practices by Sun et al[35] revealed significant improvements in gut microbiota composition, which were linked to reduced anxiety and depression, as well as enhanced immune function. This again underscores the potential of psychological interventions, such as CBT and meditation, in addressing mental health challenges through both psychological and physiological mechanisms.

Rivera-Romero et al[36] reviewed mobile health (mHealth) solutions for supporting hypertensive disorders during pregnancy. It aimed to identify relevant protocols and prototypes to improve clinical practice. The review included 11 articles, finding positive results in maternal health improvement and solution acceptability, though most studies were small and lacked clinical validation. The study concluded that mHealth solutions have great potential but need rigorous clinical trials for integration into healthcare systems, especially in low-resource settings.

Pharmacological treatment

The statement published by the American Heart Association in 2022 summarized the pharmacological treatment of HDPs. Initial monotherapy usually employs first-line drugs such as labetalol or methyldopa. Some guidelines support the use of nifedipine as an initial treatment option. For women with severe hypertension, common approaches include intravenous labetalol, intravenous methyldopa, and oral nifedipine. In resource-limited countries, labetalol, mid-acting nifedipine, and methyldopa have been successfully used. Diuretics are generally not used in pregnant women due to concerns about volume depletion and vasoconstriction, although recent guidelines acknowledge their potential use in specific circumstances. The article emphasizes the need for more research on the safety of antihypertensive drugs during pregnancy, as current data are limited and sometimes contradictory. In recent years, metformin, a first-line treatment for type 2 diabetes, has demonstrated a significant reduction in the incidence of gestational hypertension and preeclampsia in clinical trials. Although existing clinical data provide preliminarily evidence supporting the safety of taking metformin use during pregnancy, further research is required to refine study protocols and confirm long-term outcomes[37]. Additionally, research on antiplatelet drug use during pregnancy has highlighted complex safety considerations. When selecting antithrombotic therapy for the management or prevention of thrombotic complications during pregnancy, clinicians must account for the unique physiological adaptations of pregnancy, which influence drug pharmacokinetics, placental transfer, and potential teratogenic effects on the fetus. Although the efficacy and safety of aspirin during pregnancy have been relatively well established through numerous clinical studies, knowledge of newer, more potent antiplatelet drugs is primarily derived from individual clinical case reports, often prompted by the urgent need for potent antiplatelet therapy during pregnancy[38]. Antianxiety agents, particularly SNRIs, may impact placental vascular regulation, thereby increasing the risk of HDP. Studies suggest a significant association between SNRI use in late pregnancy and HDP occurrence, potentially due to the drugs' noradrenaline-stimulating effects, which enhance vascular reactivity[39]. Moreover, SNRI use may affect not only maternal blood pressure regulation but also fetal cardiovascular development. Research indicates that SNRI exposure is associated with structural and functional changes in the fetal heart, potentially increasing the risk of congenital heart defects[40]. Additionally, these drugs may impair fetal growth and development by altering placental blood flow and oxygen supply[41]. Treatment decisions for HDP should be individualized, considering other risk factors and patient preferences[42].

FIGO Best Practice Advice points out that anti-platelet agents (mainly low-dose aspirin) have been proven to reduce the risk of preeclampsia and the delivery of small-for-gestational-age neonates. However, the effects of aspirin on other cardiovascular events in women with a history of HDP remain uncertain, and its use for the primary prevention of cardiovascular disease is not currently recommended due to the increased risk of major bleeding events. Statins have not been shown to reduce the risk of cardiovascular events in these women. The article emphasizes the need for further research to confirm these findings and to determine the efficacy of pharmacological interventions for the primary prevention of long-term cardiovascular events in women with a history of HDP[43].

Multidisciplinary collaboration

The management of gestational hypertension requires a multidisciplinary approach, involving obstetricians, maternal-fetal medicine specialists, neonatologists, nephrologists, cardiologists, pharmacists, and nurses. In particular, coordinated care led by nurses and midwives who are responsible for case management can improve health outcomes. During hospitalization, nurses identify changes in the condition of pregnant and postpartum women through the use of early warning scores and blood pressure measurement tools, ensuring timely communication with physicians or senior nurses. These practices have been proven to reduce maternal mortality caused by hypertensive disorders.

Gama et al[44] conducted a retrospective analysis of the outcomes of patients with complications of HDP admitted to the intensive care unit (ICU) of a tertiary hospital in South Africa. The study analyzed the mortality and adverse neurological outcomes of85 patients admitted to the ICU for HDP between 2010 and 2013. The findings revealed an overall mortality rate of 11.6% and an incidence of adverse neurological outcomes of 8.99%. Factors significantly associated with mortality included intra- or postpartum seizures, twin pregnancy, failure to perform operative delivery when indicated, lowest Glasgow Coma Scale (GCS) score < 10, failure to use magnesium sulphate when indicated, respiratory failure, and lower respiratory tract infections. Factors associated with poor outcomes (adverse neurological outcomes or death) included primiparity (better outcomes in primiparous patients), earlier onset of antenatal hypertension, human immunodeficiency virus infection, failure to perform operative delivery when indicated, lowest GCS score < 10, failure to use magnesium sulphate when indicated, and the use of anticonvulsants other than magnesium sulphate or benzodiazepines in eclampsia. The study indicates that despite existing recommendations, the mortality rate of HDP in the ICU has not decreased over the past decade, suggesting the need for improved implementation of management protocols.

CONCLUSION

HDP are among the leading causes of morbidity and mortality in pregnant women during the perinatal period. The association between HDP and psychological factors, such as anxiety, is increasingly recognized. Studies have shown that anxiety not only increases the risk of HDP through various pathways, including neuroendocrine, inflammatory, and autonomic nervous system mechanisms, but also exacerbates its clinical manifestations by affecting blood pressure regulation and vascular function, which are further linked to adverse cardiovascular outcomes. Psychological interventions (such as cognitive-behavioral therapy and mindfulness meditation) and pharmacological treatments (such as labetalol and nifedipine) play important roles in alleviating anxiety and improving the prognosis of HDP. Multidisciplinary collaboration models (e.g., HDP care units) and postpartum long-term care (e.g., cardiac metabolic assessment and dynamic blood pressure monitoring) are also crucial for reducing the long-term risk of cardiovascular diseases. Table 1 summarizes the relationship, mechanisms, and management of HDP. Despite significant progress in recent years in research on anxiety and HDP, many issues require further exploration. Future research should focus on the following aspects: (1) In-depth exploration of mechanisms, as the biological mechanisms linking anxiety and HDP are not yet fully understood; (2) Optimization of clinical interventions, as the effectiveness and safety of psychological and pharmacological interventions need further validation through randomized clinical trials; (3) Improvement of multidisciplinary collaboration models to achieve more comprehensive patient management and better treatment outcomes; (4) The importance of long-term follow-up studies to assess the long-term health impacts of anxiety and HDP on mothers and infants; and (5) The impact of cultural and social factors on anxiety and HDP, particularly in different cultural contexts and the role of social support systems in improving prognosis[45-47].

Table 1 Anxiety and hypertensive disorders of pregnancy: Relationship, mechanisms, and management.

Category	Details
Epidemiology	Anxiety is significantly associated with HDP, increasing the risk of HDP (OR = 1.324), preeclampsia (OR = 1.522), and eclampsia (OR = 1.813)
	Global prevalence of HDP: 6.3% in the United States, 8.0% in China
	Anxiety prevalence: 13.6% in the United States, 16% in China
	Anxiety rates among immigrant women from low-income countries can reach up to 31%
Potential mechanisms	Neuroendocrine mechanisms: Anxiety activates the HPA axis, increasing cortisol levels and enhancing renin-angiotensin system activity, leading to vasoconstriction and elevated blood pressure
	Inflammatory mechanisms: Anxiety promotes the release of proinflammatory cytokines (e.g., TNF-α, IL-6, IL-17), impairing vascular endothelial function and promoting oxidative stress
	Genetic and epigenetic mechanisms: HDP-associated genetic variants (e.g., angiotensinogen gene mutations) increase cardiovascular risk
	Gut microbiota and metabolic regulation: Anxiety-induced gut microbiota dysbiosis affects blood pressure regulation through the "gut-brain-vascular axis"
	Autonomic nervous system and hemodynamic changes: Anxiety-induced sympathetic overactivation reduces heart rate variability and increases vascular resistance
Treatment and management	Psychological Interventions: Relaxation training, yoga, and mindfulness meditation significantly reduce blood pressure and stress
	Pharmacological treatment: First-line drugs like labetalol and nifedipine are used for HDP management; SNRIs may increase HDP risk
	Multidisciplinary collaboration: Obstetricians, psychologists, nutritionists, and other specialists collaborate to optimize patient management
Long-term risks	HDP is associated with increased long-term risks of cardiovascular disease, chronic kidney disease, and metabolic syndrome
	Anxiety exacerbates these risks through persistent activation of inflammatory pathways and endothelial dysfunction
Future research directions	Mechanistic Studies: Further explore neuroendocrine, inflammatory, and autonomic nervous system pathways linking anxiety and HDP
	Optimization of Interventions: Validate the effectiveness and safety of psychological and pharmacological interventions through RCTs
	Multidisciplinary collaboration models: Improve integration of resources from obstetrics, psychology, and nutrition for personalized treatment plans
	Long-term follow-up studies: Assess the long-term health impacts of anxiety and HDP on mothers and infants
	Cultural and social factors: Examine the role of sociocultural stressors and support systems in anxiety and HDP

HDP: Hypertensive disorders of pregnancy; HPA: Hypothalamic-pituitary-adrenal; IL: Interleukin; OR: Odds ratio; RCTs: Randomized clinical trials; SNRIs: Serotonin-norepinephrine reuptake inhibitors; TNF-α: Tumor necrosis factor alpha.