Hypertension as a Predictor of Ovarian Cancer Risk: A Systematic Review and Meta‐Analysis

ABSTRACT

Background and Aims

Ovarian cancer is a primary contributor to cancer‐related deaths among women and holds a position among the most common gynecological malignancies worldwide. While hypertension has been identified as a potential risk factor for various cancers, its association with ovarian cancer remains inconclusive. This systematic review and meta‐analysis synthesized data from observational studies to provide light on the association between hypertension and the risk of ovarian cancer.

Methods

This study followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines and secured registration with the PROSPERO under the identifier CRD42025636649. A systematic literature search of PubMed, Embase, and Web of Science was conducted to identify observational studies published through December 10, 2024. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random‐effects model. Heterogeneity was assessed using the I² statistic, and subgroup analyses were conducted based on study design, parity, and body mass index (BMI).

Results

Out of 2686 articles identified, 11 studies with a total of 2,523,751 participants met the inclusion criteria. There was a risk ratio (RR) of 1.06 (95% CI, 0.96–1.20) for ovarian cancer in patients with hypertension, and considerable heterogeneity was noted (I² = 81%). Within the subgroup analyses, it was noted that parity played a role in reducing ovarian cancer risk (RR, 1.43; 95% CI, 1.05–1.96; p = 0.0025), while obesity (BMI ≥ 25 kg/m²) was associated with an increased risk (RR, 1.12; 95% CI, 1.07–1.18; p < 0.001). No significant associations were found for diabetes, menopausal status, or smoking.

Conclusion

There is no statistically significant association between high blood pressure and the risk of ovarian cancer, according to this meta‐analysis. To confirm these results, additional research utilizing larger participant groups and robust study designs is essential.

Abbreviations

DBP

diastolic blood pressure

NOS

Newcastle–Ottawa scale

RAAS

renin‐angiotensin‐aldosterone system

ROS

oxygen free radicals/reactive oxygen species

SBP

systolic blood pressure

VEGF

vascular endothelial growth factor

1. Introduction

Worldwide, ovarian cancer ranks as the eighth most commonly occurring malignancy in women and is the fifth primary cause of cancer‐associated fatalities within this population [1, 2]. Despite a global annual decrease in mortality since the 1990s, ranging from approximately 1%–2.4%, regional disparities persist. The decline in mortality rates is largely attributed to decreased incidence rates, influenced by increased usage of oral birth control pills and a reduction in hormone replacement therapy [3, 4]. However, in well‐developed and economically transitioning countries, such as those in Eastern and Southern Europe and Japan, the incidence of ovarian cancer has risen, potentially linked to reduced pregnancy rates and shorter durations of breastfeeding [5].

The majority of ovarian cancers are epithelial in origin, classified into five major types of carcinomas: high‐grade serous (70%), low‐grade serous (3%), endometrioid (12%), clear cell (12%), and mucinous (3%) [6, 7]. While the prevalence of these subtypes remains consistent globally, variations exist in Asian countries where clear cell and endometrioid carcinomas are more prevalent. Diagnosing ovarian cancer is challenging due to its nonspecific symptoms and the absence of reliable screening tests, often leading to late‐stage detection and poor prognoses [8, 9, 10]. Established risk factors for ovarian cancer include higher body mass index (BMI), older age, genetic mutations (BRCA1/BRCA2), hormone replacement therapy, nulliparity, tobacco use, endometriosis, and diabetes [11, 12, 13]. Conversely, the use of oral contraceptives and metformin has been associated with a reduced risk [14, 15, 16, 17].

Hypertension, affecting approximately 45% of the American population and showing an increasing trend in other regions such as the European Union, is a major global health concern and a known risk factor for several cancers [18]. The relationship between hypertension and cancer development may be mediated through several mechanisms, including extracellular matrix remodeling, altered secretion of vascular endothelial growth factor (VEGF), increased levels of oxygen‐free radicals (ROS), and the influence of the renin‐aldosterone‐angiotensin system (RAAS) and matrix metalloproteinases (MMPs) [18, 19, 20]. Existing research has not clarified the link between hypertension and ovarian cancer. This comprehensive systematic review and meta‐analysis seeks to clarify the possible connection between elevated blood pressure and ovarian cancer risk, ultimately improving understanding of its pathogenesis and guiding prevention and treatment efforts.

2. Methods

The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA 2020) standards were used in the compilation of this meta‐analysis and the protocol was registered with PROSPERO (CRD42025636649) [21] (Table S1).

2.1. Literature Search

A comprehensive search was conducted across PubMed, Embase, and Web of Science to identify studies on the association between hypertension and ovarian cancer risk. This search included articles from the inception of each database up to December 10, 2024. The search terms used were “hypertension” AND “ovarian cancer.” To ensure an exhaustive review, references of the included studies were also examined (Table S2).

2.2. Eligibility Criteria

Our meta‐analysis solely incorporated original research, published in English up to July 2024, that examined the connection between high blood pressure and the risk of developing ovarian cancer. These researches had to satisfy specific conditions: (i) they were a cohort design (either prospective or retrospective) or a case‐control; (ii) presented risk assessments (relative risks, hazard ratios, odds ratios) and 95% confidence intervals; (iii) containing the following data: number of women with hypertension who developed ovarian cancer and number of women with hypertension who did not develop ovarian cancer and number of patients without hypertension who developed ovarian cancer and the number of patients without hypertension who did not develop ovarian cancer.

2.3. Screening and Data Extraction

The screening was conducted using Nested Knowledge software to review titles, abstracts, and full texts [22]. Duplicates were removed, and eligibility was assessed based on predefined criteria. Two researchers worked independently, resolving disagreements through discussion. Data extraction focused on study details and population characteristics, with additional reviews ensuring accuracy.

2.4. Quality Assessment

To gauge the risk of bias in the studies, the Newcastle‐Ottawa Scale (NOS) [23, 24] was utilized. Assessment focused on selection, comparability, and outcome or exposure. Items in selection and exposure categories could receive up to 1 star, and comparability could receive up to 2 stars, with a maximum score of 9. Studies scoring 7 or more were considered high quality, while scores of 0–3 indicated low quality and 4–6 medium quality.

2.5. Statistical Analysis

The meta‐analysis was executed using R software. For each individual study, risk ratios (RRs) were computed along with their 95% confidence intervals. Subsequently, A meta‐analysis using the DerSimonian‐Laird random effects model [25, 26] was carried out. Heterogeneity was evaluated using the I ² statistic, with values above 75% indicating high heterogeneity, 50%–75% moderate, and below 50% low [27]. To assess publication bias, Egger's linear regression and Begg's rank correlation tests were employed [28, 29], along with visual inspection of funnel plot symmetry [30, 31].

3. Results

3.1. Literature Search

A total of 2047 records were identified (742) from Embase, 855 from PubMed, and 450 from Web of Science). After removing 312 duplicates, 1735 records were screened, with 1699 excluded. Of the 36 reports retrieved, 25 full‐text articles were excluded (12 reviews, 3 lacking the population of interest, and 10 without relevant outcomes). Eleven studies were ultimately incorporated into the meta‐analysis (Figure 1).

Figure 1.

Flow diagram depicting the inclusion process aligned with PRISMA criteria.

3.2. Summary Characteristics of the Studies Included

A total of 2,523,751 participants were included, with ovarian cancer cases ranging from 133 to 16,850. All participants were women aged over 20 years. Four studies were conducted in the United States, three in Europe, one in China, one in Saudi Arabia, and one was a multicenter study (Table 1). All studies were observational, employing either case‐control or cohort designs. NOS scores ranged from 6 to 8, with a mean score of 7.3 (Table S3).

Table 1.

Basic characteristics of the studies included in the meta‐analysis.

Study	Country	Study design	Age (years)	Ovarian cancer vs. controls	Definition of hypertension
Parazzini et al. 1997 [32]	Italy	Case–control	22–74	971/2758	Not available
Soler et al. 1999 [33]	Italy	Case–control	Median: 54	970/3054	Not available
Brinton et al. 2007 [34]	Denmark	Cohort	Mean: 44	2491/99,421	Not available
Chia et al. 2013 [35]	United States	Cohort	> =66	5087/5087	Not available
Fraeman et al. 2013 [36]	United States	Cohort	Mean: 61	763/25,090	SBP > 150–mm Hg, or DBP > 100 mm Hg
Huang et al. 2016 [37]	United States	Cohort	30–50	687/1,479,857	BP ≥ 140/90 mmHg
Huang et al. 2016 [37]	United States	Cohort	25–42	261/2,210,479	BP ≥ 140/90 mmHg
Chen et al. 2017 [38]	China	Case–control	Mean: 52	573/1146	BP ≥ 140/90 mmHg
Michels et al. 2019 [39]	United States SEER‐ Medicare	Case–control	68–89	16,850/ 281,878	Not available
Staples et al. 2020 [40]	Multicenter AACES	Case–control	20–79	593/732	Not available
Alrobaiq et al. 2023 [41]	Saudi Arabia	Case–control	Mean: 57	133/137	SBP, and/or > 130–mm Hg DBP > 80 mm Hg

A stratified analysis was performed to account for covariate variations (Table 2). The findings indicated a 1.12‐fold elevated risk of ovarian cancer in individuals with a BMI ≥ 25 kg/m² compared to those with a BMI ≤ 25 kg/m² (95% CI: 1.07–1.18, p < 0.001). Additionally, a 1.43‐fold elevation in ovarian cancer risk was observed in women who had never given birth (95% CI: 1.05–1.96, p < 0.002). No statistically significant findings emerged concerning diabetes, menopausal status, or smoking.

Table 2.

Analysis stratified by potential confounding factors affecting the link between hypertension and ovarian cancer risk.

Covariates	Variable	No of studies	RR (95% CI)	p<	I 2
Parity	Gave birth	5	1.43 (1.05, 1.96)	0.0025	96.91%
	Nulliparous	5
Diabetes	Yes	4	1.27 (0.94, 1.72)	0.1155	97.99%
	No	4
Menopausal status	Postmenopausal	4	1.20 (0.89, 1.61)	0.2242	94.75%
	Premenopausal	4
Body mass index	≥ 25	4	1.12 (1.07, 1.18)	0.0001	00.00%
	< 25	4
Cigarette smoking	Yes	2	2.20 (0.53, 9.16)	0.2791	99.17%
	No	2

Abbreviations: CI, confidence interval; p < , p value for heterogeneity between subgroups; RR, relative.

3.3. Meta‐Analysis

The relationship between hypertension and ovarian cancer risk was examined in several studies, with considerable variation observed in the relative risk (RR) estimates. The pooled RR is 1.063 (95% CI: 0.961–1.176), reflecting a nonsignificant increase in risk. High heterogeneity (I² = 81%) (Figure 2). There was no indication of publication bias according to Egger's test.

Figure 2.

Forest plot representing the relationship between hypertension and ovarian cancer risk.

4. Discussions

While several investigations have delved into the association of elevated blood pressure with ovarian cancer [32, 33, 34, 35, 36, 37, 38, 39, 40, 41], conclusive evidence is still lacking. Our meta‐analysis indicates that hypertension does not significantly increase the risk of ovarian cancer, although the findings are associated with high heterogeneity (I² = 81%). As this is the initial meta‐analysis on this subject, its findings cannot be directly compared to prior research. Additionally, the study assessed other risk factors for ovarian cancer, including parity (RR = 1.43, p < 0.0025), diabetes (RR = 1.27, p < 0.1155), menopausal status (RR = 1.20, p < 0.2242), BMI (RR = 0.89, p < 0.0001), and cigarette smoking (RR = 2.20, p < 0.2791).

Hypertension has varying associations with different cancers. Zhen Liang et al. [42] found a moderate link to prostate cancer (RR = 1.08), with stronger risks in Asians (RR = 1.88), while no significant connection was seen with ovarian cancer. Agnieszka Drab et al. [43] reported a strong association with endometrial cancer (RR = 1.37) influenced by BMI ≥ 30, diabetes, and nulliparity, in contrast to ovarian cancer's lack of association. Breast cancer studies by Hedong Han et al. [44] and Thunyarat Anothaisintawee et al. [45] showed modest hypertension risks (RR = 1.15–1.20) in postmenopausal women, while breastfeeding reduced risk (RR = 0.72). Ovarian cancer risk was affected by parity and BMI but not hypertension, reflecting differing hormonal and metabolic pathways.

Chen Zhang et al. [46] and Kun Xuan et al. [47] observed moderate hypertension‐colorectal cancer links (RR = 1.07–1.15) with stronger male‐specific risks for rectal cancer (RR = 1.35), differing from ovarian cancer, where hypertension was insignificant. Jalal Poorolaja et al. [48] found no association with stomach cancer (OR = 1.00), where H. pylori infection, smoking, and salt intake were key risks. Similarly, ovarian cancer showed no hypertension link, with BMI and parity emerging as primary factors. These findings highlight hypertension's varying impact across cancers, shaped by metabolic, hormonal, and lifestyle differences.

This meta‐analysis demonstrates strengths that enhance its reliability, including adherence to PRISMA guidelines and PROSPERO registration for a systematic approach. Data from over 2.5 million participants across 10 studies provided substantial statistical power to assess the association between hypertension and ovarian cancer. Stratified analyses addressed confounders like BMI, parity, and menopausal status, offering insights into their interaction with hypertension in influencing cancer risk. Robust statistical methods, including random‐effects modeling and heterogeneity assessment, strengthened validity.

The review has a few limitations, including variability in the definition and measurement of hypertension across studies, which may have introduced misclassification bias and influenced pooled results. High heterogeneity (I² = 81%) indicates significant differences in study populations, designs, and methods. Most studies were observational, limiting causation assessment, and despite adjustments for confounders like BMI and parity, residual confounding from factors such as diet and genetic predispositions remains possible. The predominance of Western studies limits generalizability to regions with differing hypertension and ovarian cancer prevalence patterns. Language bias may have arisen from restricting the review to English‐language studies, potentially excluding relevant research, while reliance on the Newcastle–Ottawa Scale for quality assessment, despite its acceptance, may not fully capture methodological flaws or inconsistencies.

The meta‐analysis found no significant association between hypertension and ovarian cancer risk (RR = 1.06; 95% CI, 0.96–1.20), contrasting with some prior studies that reported modest associations between hypertension and other cancers, such as endometrial or breast cancer. This discrepancy may stem from several factors, including differences in study design, with our analysis including both cohort and case‐control studies, which vary in their ability to establish causality. Variations in study populations, such as geographic diversity (e.g., Western vs. Asian cohorts) and differences in baseline characteristics like age or menopausal status, could also contribute. Additionally, inconsistent adjustment for confounding variables, such as BMI, parity, or hormonal factors, across studies may obscure the relationship. The high heterogeneity (I² = 81%) observed suggests methodological differences, including variable hypertension definitions, further complicating direct comparisons. These factors highlight the need for standardized approaches in future studies to better elucidate hypertension's role in ovarian cancer risk.

For public health policy, the findings suggest that strategies to reduce ovarian cancer incidence should prioritize addressing modifiable risk factors such as obesity and smoking. However, hypertension, while not significantly associated with ovarian cancer risk in this study, remains a critical independent condition requiring effective management due to its role in metabolic syndrome and broader health implications [49].

In addressing the variability in hypertension definitions across the included studies, it is noteworthy that six of the eleven studies did not specify a definition for hypertension, while others used differing thresholds, such as systolic blood pressure ≥ 150 mmHg or diastolic ≥ 100 mmHg in one study, and systolic ≥ 130 mmHg in another. This inconsistency introduces potential misclassification bias, which may affect the reliability of the pooled results. Despite this, our inclusion criteria did not restrict studies based on specific hypertension definitions, allowing for a comprehensive analysis of all relevant data. This limitation, as acknowledged, shows the need for standardized hypertension definitions in future research to enhance comparability and applicability of findings in clinical practice, where consistent diagnostic criteria are critical for effective risk assessment and patient management.

Future research should focus on large, prospective cohort studies with standardized hypertension definitions and more robust control of confounders. Studies examining the role of hypertension in specific ovarian cancer subtypes and across diverse populations will be essential to refine these findings. Additionally, exploring the biological mechanisms linking hypertension, vascular changes, and hormonal pathways to ovarian cancer risk could provide new insights and inform targeted prevention strategies.

5. Conclusions

The present meta‐analysis delves into the prospective association between hypertension and ovarian cancer risk, ultimately revealing no noteworthy correlation. These outcomes highlight the importance of subsequent investigations that include varied populations, address confounding factors, and employ standardized methodologies to improve the precision and relevance of the findings. Further research is required to enhance our knowledge of the risk factors for ovarian cancer and to develop effective prevention strategies.

Author Contributions

Conceptualization by Wahby Mohammed Babaresh, Abdur Rahim, and Aftab Ullah. Methodology by Wahby Mohammed Babaresh, Aftab Ullah, Zakiullah, and Kayam Naveen Kumar. Software by Saikumar Gadidala, and Zakiullah. Validation by Amogh Verma, Ranjana Sah, by Bushra Sajjad. Formal analysis by Wahby Mohammed Babaresh, Aftab Ullah, and Saikumar Gadidala. Investigation by all authors. Data curation by Zia Ul Hassan, Kayam Naveen Kumar, and Rachana Mehta. Writing original draft by Wahby Mohammed Babaresh, Abdur Rahim, Aftab Ullah, and Zakiullah. Writing review and editing by all authors. Visualization by Saikumar Gadidala and Amogh Verma. Supervision by Wahby Mohammed Babaresh. Project administration by Aftab Ullah.

Funding

The authors received no specific funding for this study.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

The corresponding author, Wahby Mohammed Babaresh, affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Supporting information

Supplemetary_oviran_meta.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, Wahby Mohammed Babaresh, upon reasonable request. This data is derived from previously published studies, which are cited in the reference list.