Abstract
Objectives
To determine whether prior myomectomy reduces hypertensive disorders of pregnancy (HDP) risk in women with fibroids, and whether fibroid location modifies this risk.
Study Design
Retrospective propensity score-matched cohort study using TriNetX, a federated health record network spanning over 100 US healthcare organizations. Women aged 18–55 years attending a prenatal visit were assigned to three groups: fibroids with prior myomectomy; fibroids without myomectomy; and no fibroids (reference). Groups were matched 1:1 on age, race/ethnicity, BMI, chronic hypertension, pregestational diabetes, tobacco use, and prior assisted reproductive technology.
Main Outcome Measures
Gestational hypertension, preeclampsia, eclampsia, and superimposed preeclampsia within one year of the prenatal visit, reported as risk ratios (RR) with 95% confidence intervals. A secondary analysis examined HDP risk by fibroid location.
Results
After matching, women with fibroids without myomectomy had significantly increased risk of overall HDP (RR 1.21, 95% CI 1.17–1.25), gestational hypertension (RR 1.29, 95% CI 1.22–1.36), preeclampsia (RR 1.31, 95% CI 1.24–1.39), superimposed preeclampsia (RR 1.25, 95% CI 1.12–1.39), and eclampsia (RR 1.38, 95% CI 1.05–1.80) versus reference. Prior myomectomy similarly conferred elevated overall HDP risk (RR 1.24, 95% CI 1.12–1.37). No significant differences were observed between myomectomy and no-myomectomy groups. HDP risk was elevated across all fibroid locations, including subserosal fibroids (overall HDP RR 1.47, 95% CI 1.32–1.65).
Conclusions
Uterine fibroids are associated with increased HDP risk regardless of prior myomectomy or fibroid location, suggesting fibroids may represent a marker of systemic vascular dysfunction. Fibroid status should be incorporated into preconception and prenatal HDP risk stratification.
Keywords: uterine fibroids, leiomyoma, myomectomy, hypertensive disorders of pregnancy, preeclampsia, gestational hypertension
Introduction
Uterine fibroids, also known as leiomyomas, are among the most prevalent gynecologic conditions of reproductive age, affecting up to 80% of individuals over a lifetime.[1] Although the majority of pregnant individuals with fibroids remain asymptomatic, fibroids are associated with a range of adverse pregnancy outcomes including preterm birth, fetal growth restriction, cesarean delivery, and postpartum hemorrhage.[2,3] Hypertensive disorders of pregnancy (HDP)—encompassing gestational hypertension, preeclampsia, eclampsia, and superimposed preeclampsia—are among the most consequential complications of pregnancy and a leading cause of maternal and perinatal morbidity and mortality worldwide.[4]
Fibroids have been associated with HDP across multiple cohort studies, but the factors that modify this risk remain incompletely characterized.[5–7] Whether surgical removal of fibroids prior to conception mitigates HDP risk, and whether fibroid anatomical location identifies individuals at greater risk, remain unknown. Therefore, we aimed to evaluate the association between uterine fibroids and HDP and determine whether fibroid-specific factors, including prior myomectomy and fibroid location, modify this risk.
Methods
We conducted a retrospective cohort study using TriNetX, a federated electronic health record research network aggregating data from over 100 healthcare organizations across the United States.[8] Data were queried from the TriNetX platform in 2026, with patient records spanning from approximately 2010 to the query date. This study was deemed exempt by the Johns Hopkins University Institutional Review Board (IRB00229605) because it used de-identified data in compliance with HIPAA Section §164.514(b)(1). The study was conducted in accordance with the Declaration of Helsinki. The term ‘women’ is used throughout this manuscript to describe individuals classified as female in the electronic health record; we acknowledge that not all individuals who become pregnant identify as women.
We identified women aged 18–55 years who attended a prenatal visit, defined by a primary ICD-10 diagnostic code of Z34 (supervision of normal pregnancy). Fibroid diagnoses (ICD-10 D25.0–D25.9) were ascertained from any diagnostic field prior to the first prenatal visit. Three mutually exclusive cohorts were constructed: (1) women with a fibroid diagnosis who underwent myomectomy within five years prior to their first prenatal visit (fibroids with myomectomy group); (2) women with a fibroid diagnosis who did not undergo myomectomy prior to their first prenatal visit (fibroids without myomectomy group); and (3) pregnant women without a fibroid diagnosis or myomectomy history (reference group). Analyses were restricted to singleton pregnancies. Across all three cohorts, patients were excluded if they had a history of hysterectomy, uterine artery embolization, or multiple gestation. Temporal relationships were enforced such that fibroid diagnosis preceded the first prenatal visit in the fibroids without myomectomy group, and myomectomy occurred within five years before the first prenatal visit in the fibroids with myomectomy group. The cohort construction process is illustrated in Figure 1.
Figure 1. Study Cohort Construction and Propensity Score Matching.
Cohorts were constructed from a federated electronic health record network of over 100 US healthcare organizations. All women aged 18–55 years with a prenatal visit (ICD-10 Z34) were identified as the initial pool (n=2,564,928). Propensity score matching was performed separately for each pairwise comparison. ART, assisted reproductive technology; BMI, body mass index; ICD-10, International Classification of Diseases, 10th Revision.
Primary outcomes included gestational hypertension (O13), preeclampsia (O14), eclampsia (O15), superimposed preeclampsia (O11), and overall HDP (O10–O16), ascertained from any diagnostic field within one year of the first prenatal visit. A secondary analysis stratified the fibroids without myomectomy group by fibroid location using ICD-10 subcodes: submucosal (D25.0), intramural (D25.1, excluding D25.0), subserosal (D25.2, excluding D25.0 and D25.1), and unspecified (D25.9, excluding D25.0, D25.1, and D25.2), to ensure mutually exclusive location classification. Patients with multiple fibroid location codes were assigned to the most clinically relevant category using a hierarchical approach: submucosal codes took precedence, followed by intramural, then subserosal, with unspecified assigned only when no specific location code was present. Each fibroid location subtype was compared independently to the reference group (no fibroids) to assess whether HDP risk elevation was present across all anatomical locations.
Propensity score matching was performed using the TriNetX platform, which utilizes logistic regression to estimate the probability of cohort membership based on user-specified covariates.[8] Patients were matched 1:1 using greedy nearest-neighbor matching without replacement, with a caliper width of 0.1. Three separate matched comparisons were performed: fibroids without myomectomy versus reference (28,346 matched pairs), fibroids with myomectomy versus reference (2,762 matched pairs), and fibroids with myomectomy versus fibroids without myomectomy (2,764 matched pairs). Matching variables included age at first prenatal visit, race and ethnicity, body mass index (BMI) at first prenatal visit, chronic hypertension, pregestational diabetes, tobacco use, and prior assisted reproductive technology. Outcomes were reported as risk ratios (RR) with 95% confidence intervals (CI). Figures were generated using R (version 4.5.1) with the ggplot2 and patchwork packages (RStudio version 2025.09.2+418, Posit Software).
ICD-10 and CPT codes used to define exposures and outcomes are provided in Supplemental Materials.
Results
Baseline characteristics before and after propensity score matching are shown in Table 1; covariates were well-balanced after matching. Compared to the reference group, women with fibroids who did not undergo myomectomy demonstrated significantly increased risk across HDP outcomes (Table 2, Figure 2A). Overall HDP risk was elevated (RR 1.21, 95% CI 1.17–1.25), as were risks for gestational hypertension (RR 1.29, 95% CI 1.22–1.36), preeclampsia (RR 1.31, 95% CI 1.24–1.39), superimposed preeclampsia (RR 1.25, 95% CI 1.12–1.39), and eclampsia (RR 1.38, 95% CI 1.05–1.80).
Table 1. Baseline Characteristics of Study Cohorts Before and After Propensity Score Matching.
Panel A: before matching. Panel B: after matching. Matching was performed separately for three pairwise comparisons; the reference column in Panel B reflects the fibroids without myomectomy comparison (28,346 matched pairs). Propensity score matching was performed 1:1 using greedy nearest-neighbor matching without replacement on age, race and ethnicity, BMI, chronic hypertension, pregestational diabetes, tobacco use, and prior assisted reproductive technology (ART). Blood pressure is descriptive only. BMI, body mass index; SD, standard deviation.
| Panel A: Baseline Characteristics Before Propensity Score Matching | ||||
|---|---|---|---|---|
|
| ||||
| Characteristic | Reference (No Fibroids) | Fibroids Without Myomectomy | Fibroids With Myomectomy | |
|
| ||||
| Total N | 2,365,348 | 28,621 | 2,825 | |
| Age, mean (SD), years | 28 ± 5.97 | 34 ± 5.17 | 35.2 ± 4.55 | |
| Race, n (%) | ||||
| White | 1,203,767 (50.89%) | 10,569 (36.93%) | 1,167 (41.31%) | |
| Black | 391,063 (16.53%) | 9,397 (32.83%) | 870 (30.80%) | |
| Asian | 120,950 (5.11%) | 2,365 (8.26%) | 272 (9.63%) | |
| American Indian | 14,011 (0.59%) | 121 (0.42%) | 10 (0.35%) | |
| Hispanic or Latino | 343,163 (14.51%) | 3,118 (10.89%) | 263 (9.31%) | |
| Other/Unknown | 356,070 (15.05%) | 4,368 (15.26%) | 338 (11.97%) | |
| BMI, mean (SD), kg/m2 | 28.6 ± 7.43 | 30.3 ± 7.68 | 29.2 ± 7.11 | |
| Blood pressure, mean (SD), mmHg | ||||
| Systolic | 117 ± 13.5 | 119 ± 14.1 | 120 ± 14.5 | |
| Diastolic | 71.6 ± 10.5 | 74.1 ± 10.9 | 73.6 ± 10.6 | |
| Chronic hypertension, n (%) | 55,016 (2.33%) | 2,486 (8.69%) | 294 (10.41%) | |
| Pregestational diabetes, n (%) | 45,892 (1.94%) | 1,439 (5.03%) | 107 (3.79%) | |
| Tobacco use, n (%) | 26,229 (1.11%) | 541 (1.89%) | 46 (1.63%) | |
| Prior ART, n (%) | 11,314 (0.48%) | 923 (3.23%) | 209 (7.40%) | |
|
Panel B: Baseline Characteristics After Propensity Score Matching | ||||
| Characteristic | Reference (No Fibroids) | Fibroids Without Myomectomy | Fibroids With Myomectomy | |
|
| ||||
| Matched pairs | 28,346 | 28,346 | 2,762 | |
| Age, mean (SD), years | 34 ± 5.17 | 34 ± 5.17 | 35.2 ± 4.54 | |
| Race, n (%) | ||||
| White | 10,581 (37.33%) | 10,569 (37.29%) | 1,167 (42.25%) | |
| Black | 9,397 (33.15%) | 9,389 (33.12%) | 869 (31.46%) | |
| Asian | 2,363 (8.34%) | 2,365 (8.34%) | 272 (9.85%) | |
| American Indian | 115 (0.41%) | 121 (0.43%) | 10 (0.36%) | |
| Hispanic or Latino | 3,117 (11.00%) | 3,118 (11.00%) | 262 (9.49%) | |
| Other/Unknown | 4,372 (15.42%) | 4,368 (15.41%) | 337 (12.20%) | |
| BMI, mean (SD), kg/m2 | 29.9 ± 7.87 | 30.3 ± 7.68 | 29.2 ± 7.10 | |
| Blood pressure, mean (SD), mmHg | ||||
| Systolic | 118 ± 14.8 | 119 ± 14.4 | 118 ± 14.1 | |
| Diastolic | 72.6 ± 10.9 | 73 ± 10.6 | 73.3 ±10.6 | |
| Chronic hypertension, n (%) | 2,477 (8.74%) | 2,480 (8.75%) | 292 (10.57%) | |
| Pregestational diabetes, n (%) | 1,034 (3.65%) | 1,040 (3.67%) | 105 (3.80%) | |
| Tobacco use, n (%) | 545 (1.92%) | 541 (1.91%) | 46 (1.67%) | |
| Prior ART, n (%) | 894 (3.15%) | 919 (3.24%) | 207 (7.50%) | |
Table 2. Risk of Hypertensive Disorders of Pregnancy by Fibroid and Myomectomy Status.
Risk ratios (RR) with 95% confidence intervals and p-values following propensity score matching. Eclampsia could not be assessed in Panels B and C due to insufficient events. HDP, hypertensive disorders of pregnancy (ICD-10 O10–O16). PE, preeclampsia.
|
Panel A. Fibroids without Myomectomy vs. Reference (N = 28,346 matched pairs)
| ||||
|---|---|---|---|---|
| Outcome | Fibroid n (%) | Reference n (%) | Risk Ratio (95% CI) | p-value |
|
| ||||
| Gestational Hypertension | 2,544 (8.97%) | 2,052 (7.24%) | 1.29 (1.22, 1.36) | <0.001 |
| Preeclampsia | 2,169 (7.65%) | 1,615 (5.70%) | 1.31 (1.24, 1.39) | <0.001 |
| Eclampsia | 126 (0.44%) | 81 (0.29%) | 1.38 (1.05, 1.80) | 0.018 |
| Superimposed PE | 649 (2.29%) | 522 (1.84%) | 1.25 (1.12, 1.39) | <0.001 |
| Overall HDP | 6,046 (21.33%) | 4,969 (17.53%) | 1.21 (1.17, 1.25) | <0.001 |
|
Panel B. Fibroids with Myomectomy vs. Reference (N = 2,762 matched pairs) | ||||
| Outcome | Fibroid n (%) | Reference n (%) | Risk Ratio (95% CI) | p-value |
|
| ||||
| Gestational Hypertension | 265 (9.59%) | 221 (8.00%) | 1.19 (1.01, 1.42) | 0.037 |
| Preeclampsia | 242 (8.76%) | 190 (6.89%) | 1.27 (1.06, 1.53) | 0.009 |
| Eclampsia | N/A | N/A | N/A | N/A |
| Superimposed PE | 76 (2.75%) | 57 (2.06%) | 1.33 (0.95, 1.87) | 0.095 |
| Overall HDP | 688 (24.91%) | 556 (20.13%) | 1.24 (1.12, 1.37) | <0.001 |
|
Panel C. Fibroids with Myomectomy vs. Fibroids without Myomectomy (N = 2,764 matched pairs) | ||||
| Outcome | Myomectomy n (%) | No Myomectomy n (%) | Risk Ratio (95% CI) | p-value |
|
| ||||
| Gestational Hypertension | 265 (9.59%) | 272 (9.84%) | 0.97 (0.83, 1.14) | 0.751 |
| Preeclampsia | 242 (8.76%) | 253 (9.15%) | 0.96 (0.81, 1.13) | 0.604 |
| Eclampsia | N/A | N/A | N/A | N/A |
| Superimposed PE | 77 (2.79%) | 89 (3.22%) | 0.87 (0.64, 1.17) | 0.344 |
| Overall HDP | 689 (24.93%) | 694 (25.11%) | 0.99 (0.91, 1.10) | 0.877 |
Figure 2. Risk of Hypertensive Disorders of Pregnancy by Fibroid and Myomectomy Status.
Forest plots showing risk ratios (RR) with 95% confidence intervals following propensity score matching. Event counts shown as fibroid group n / reference group n. (A) Fibroids without myomectomy vs. reference (28,346 matched pairs); (B) Fibroids with myomectomy vs. reference (2,762 matched pairs); (C) Fibroids with myomectomy vs. fibroids without myomectomy (2,764 matched pairs). Eclampsia could not be assessed in Panels B and C due to insufficient events. HDP, hypertensive disorders of pregnancy; HTN, hypertension; PE, preeclampsia.
Women with fibroids who underwent myomectomy prior to the first prenatal visit similarly demonstrated elevated HDP risk compared to the reference group (Table 2, Figure 2B). Overall HDP risk was significantly increased (RR 1.24, 95% CI 1.12–1.37), as were risks for gestational hypertension (RR 1.19, 95% CI 1.01–1.42) and preeclampsia (RR 1.27, 95% CI 1.06–1.53). Risk of superimposed preeclampsia was elevated but did not reach statistical significance (RR 1.33, 95% CI 0.95–1.87, p=0.095). Eclampsia could not be assessed in this comparison due to insufficient events, per TriNetX data privacy thresholds.
No statistically significant differences in HDP risk were observed between women with fibroids who underwent myomectomy and those who did not (Table 2, Figure 2C). Risk ratios for overall HDP (RR 0.99, 95% CI 0.91–1.10, p=0.877), gestational hypertension (RR 0.97, 95% CI 0.83–1.14, p=0.751), preeclampsia (RR 0.96, 95% CI 0.81–1.13, p=0.604), and superimposed preeclampsia (RR 0.87, 95% CI 0.64–1.17, p=0.344) were all near unity. Eclampsia could not be assessed in this comparison due to insufficient events.
In the secondary analysis stratified by fibroid location within the fibroids without myomectomy group, elevated HDP risk was observed across all four fibroid locations compared to the reference group (Table 3, Figure 3). Women with subserosal fibroids demonstrated substantial HDP risk elevation, with an overall HDP risk ratio of 1.47 (95% CI 1.32–1.65) and a superimposed preeclampsia risk ratio of 2.14 (95% CI 1.45–3.17). Submucosal and intramural fibroids demonstrated overall HDP risk ratios of 1.31 (95% CI 1.16–1.47) and 1.28 (95% CI 1.19–1.37), respectively, with significant risk elevations across most individual HDP outcomes. Women with unspecified fibroids demonstrated smaller but statistically significant elevations in overall HDP (RR 1.13, 95% CI 1.07–1.18), gestational hypertension, and preeclampsia. Eclampsia could not be assessed in the subserosal and submucosal groups due to insufficient events.
Table 3. Risk of Hypertensive Disorders of Pregnancy Stratified by Fibroid Anatomical Location.
Risk ratios (RR) with 95% confidence intervals and p-values for women with fibroids without prior myomectomy compared to the reference group, stratified by fibroid location. Each comparison reflects a separate propensity score-matched analysis. Eclampsia could not be assessed in the subserosal and submucosal groups due to insufficient events. HDP, hypertensive disorders of pregnancy (ICD-10 O10–O16). PE, preeclampsia.
|
Panel A. Subserosal (N = 2,525 matched pairs)
| ||||
|---|---|---|---|---|
| Outcome | Fibroid n (%) | Reference n (%) | Risk Ratio (95% CI) | p-value |
|
| ||||
| Gestational Hypertension | 314 (12.44%) | 207 (8.20%) | 1.52 (1.28, 1.79) | <0.001 |
| Preeclampsia | 279 (11.05%) | 152 (6.02%) | 1.84 (1.52, 2.22) | <0.001 |
| Eclampsia | N/A | N/A | N/A | N/A |
| Superimposed PE | 77 (3.05%) | 36 (1.43%) | 2.14 (1.45, 3.17) | <0.001 |
| Overall HDP | 698 (27.64%) | 476 (18.85%) | 1.47 (1.32, 1.65) | <0.001 |
|
Panel B. Intramural (N = 5,960 matched pairs) | ||||
| Outcome | Fibroid n (%) | Reference n (%) | Risk Ratio (95% CI) | p-value |
|
| ||||
| Gestational Hypertension | 648 (10.87%) | 452 (7.58%) | 1.43 (1.28, 1.61) | <0.001 |
| Preeclampsia | 537 (9.01%) | 385 (6.46%) | 1.34 (1.19, 1.51) | <0.001 |
| Eclampsia | 29 (0.49%) | 22 (0.37%) | 1.32 (0.76, 2.29) | 0.326 |
| Superimposed PE | 167 (2.80%) | 117 (1.96%) | 1.43 (1.13, 1.80) | 0.003 |
| Overall HDP | 1,477 (24.78%) | 1,156 (19.40%) | 1.28 (1.19, 1.37) | <0.001 |
|
Panel C. Submucosal (N = 2,110 matched pairs) | ||||
| Outcome | Fibroid n (%) | Reference n (%) | Risk Ratio (95% CI) | p-value |
|
| ||||
| Gestational Hypertension | 295 (9.24%) | 135 (6.40%) | 1.44 (1.17, 1.78) | <0.001 |
| Preeclampsia | 177 (8.39%) | 134 (6.35%) | 1.32 (1.06, 1.64) | 0.011 |
| Eclampsia | N/A | N/A | N/A | N/A |
| Superimposed PE | 61 (2.89%) | 36 (1.71%) | 1.69 (1.13, 2.55) | 0.010 |
| Overall HDP | 509 (24.12%) | 390 (18.48%) | 1.31 (1.16, 1.47) | <0.001 |
|
Panel D. Unspecified (N = 13,378 matched pairs) | ||||
| Outcome | Fibroid n (%) | Reference n (%) | Risk Ratio (95% CI) | p-value |
|
| ||||
| Gestational Hypertension | 1,054 (7.89%) | 916 (6.85%) | 1.15 (1.06, 1.26) | 0.001 |
| Preeclampsia | 993 (7.42%) | 884 (6.61%) | 1.12 (1.03, 1.23) | 0.009 |
| Eclampsia | 55 (0.41%) | 42 (0.31%) | 1.31 (0.88, 1.96) | 0.186 |
| Superimposed PE | 312 (2.33%) | 276 (2.06%) | 1.13 (0.96, 1.33) | 0.133 |
| Overall HDP | 2,729 (20.40%) | 2,426 (18.13%) | 1.13 (1.07, 1.18) | <0.001 |
Figure 3. Risk of Hypertensive Disorders of Pregnancy Stratified by Fibroid Anatomical Location.
Forest plots showing risk ratios (RR) with 95% confidence intervals for women with fibroids without prior myomectomy compared to the reference group, stratified by fibroid location: (A) Subserosal; (B) Intramural; (C) Submucosal; (D) Unspecified. Event counts shown as fibroid group n / reference group n. Each panel reflects a separate propensity score-matched analysis. Eclampsia could not be assessed in Panels A and C due to insufficient events. HDP, hypertensive disorders of pregnancy; HTN, hypertension; PE, preeclampsia.
Discussion
Uterine fibroids were associated with significantly increased risk of hypertensive disorders of pregnancy. This elevated risk persisted regardless of myomectomy history. No significant difference in HDP risk was observed between women with fibroids who underwent myomectomy and those who did not, indicating that prior myomectomy does not modify fibroid-associated HDP risk. In the analysis stratified by fibroid location, elevated HDP risk was observed across all four anatomical locations, including subserosal fibroids located on the uterine serosa distant from the endometrial cavity. The consistency of HDP risk elevation across all fibroid locations, combined with the persistence of risk following myomectomy, supports a model in which fibroids represent a marker of systemic vascular dysfunction rather than acting solely through mechanical effects.
The observed association between uterine fibroids and HDP is consistent with prior literature. In a prospective cohort of 2,277 pregnant women, Chen et al. found that fibroids diagnosed before 20 weeks of gestation were associated with a nearly three-fold increased risk of HDP after multivariable adjustment (aHR 2.95, 95% CI 1.35–6.44).[5] Longitudinal blood pressure measurements were also significantly increased in the fibroid group throughout pregnancy.[5] Lee et al. reported modestly elevated preeclampsia risk among women with a fibroid diagnosis compared to those without in a nationwide Korean cohort of nearly 790,000 deliveries.[9] Farland et al., in a registry linkage study of over 91,000 deliveries in Massachusetts, observed a similar directional association that did not reach statistical significance, potentially reflecting differences in cohort composition and the inability to examine fibroid location, a limitation the authors explicitly noted.[10] The present study extends these findings and is the first to examine both myomectomy and fibroid location as modifiers of fibroid-associated HDP risk in a diverse US population.
Whether myomectomy modifies HDP risk in subsequent pregnancies has not been well studied. In a retrospective cohort study using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample, Ginod et al. found lower rates of gestational hypertension (aOR 0.87, 95% CI 0.77–0.97) and eclampsia (aOR 0.76, 95% CI 0.32–0.81) among women who underwent myomectomy compared to those with fibroids in situ.[6] However, that study did not include a reference group without fibroids, precluding conclusions about whether myomectomy restores baseline vascular risk. Lee et al. included a reference group and found that women with myomectomy history did not have significantly reduced preeclampsia risk compared to women without fibroids (aOR 1.16, 95% CI 1.00–1.34), suggesting that myomectomy does not fully restore baseline risk, a finding consistent with the present study.[9] The present study extends prior work by directly comparing women with fibroids who underwent myomectomy against those who did not, isolating the contribution of surgical intervention. The persistence of elevated HDP risk in both groups relative to the reference population, and the absence of risk reduction when comparing myomectomy to no myomectomy directly, indicate that myomectomy does not reverse the vascular phenotype associated with fibroids.
Existing literature emphasizes the role of submucosal fibroids in reproductive outcomes mediated by endometrial cavity distortion, such as miscarriage, preterm birth, and placental abruption.[11] To our knowledge, no prior study has examined fibroid location as a modifier of HDP risk with adequate statistical power. The present study found elevated risk across all fibroid locations. Subserosal fibroids demonstrated substantial risk elevation (overall HDP RR 1.47, 95% CI 1.32–1.65; superimposed preeclampsia RR 2.14, 95% CI 1.45–3.17), with risk magnitudes comparable to submucosal (RR 1.31, 95% CI 1.16–1.47) and intramural fibroids (RR 1.28, 95% CI 1.19–1.37). Given that subserosal fibroids are positioned on the uterine serosa distant from the endometrial cavity and placental implantation site, this pattern of consistent risk elevation across all locations suggests mechanisms extending beyond local mechanical disruption.
Several biological mechanisms may underlie these findings. Uterine fibroids are associated with systemic vascular dysfunction even outside of pregnancy.[12–14] Women with fibroids demonstrate activation of the renin-angiotensin system, with upregulation of angiotensin II and angiotensin II type 1 receptors, pathways central to both fibroid proliferation and hypertensive disease.[15,16] Endothelin-1, a potent vasoconstrictor implicated in preeclampsia pathogenesis, is overexpressed in fibroid tissue.[17,18] Vascular endothelial growth factor (VEGF) dysregulation characterizes both fibroid pathophysiology and defective placentation in preeclampsia.[19,20] Epidemiologically, women with fibroids exhibit elevated baseline blood pressure, increased arterial stiffness, and higher rates of chronic hypertension independent of body mass index.[12,21,22] Fibroids and cardiovascular disease share common risk factors including obesity, metabolic syndrome, and chronic inflammation.[13,23] Thus, fibroids and HDP may arise from shared vascular substrates rather than representing a direct causal pathway. Myomectomy removes fibroid tissue but does not reverse systemic vascular dysfunction, explaining the persistence of HDP risk following surgery. Similarly, the consistency of risk across all fibroid locations reflects the systemic nature of the underlying vascular phenotype rather than location-specific mechanical effects.
These findings have clinical implications for prenatal risk stratification, antenatal surveillance, and counseling of women with a history of uterine fibroids. Uterine fibroids, regardless of myomectomy history or anatomical location, should be considered an important marker for identifying pregnancies at elevated risk of hypertensive disorders. Women who undergo myomectomy prior to conception should be counseled that while surgical removal may address mechanical symptoms, it does not appear to mitigate HDP risk. Subserosal fibroids, despite their distance from the endometrial cavity, were associated with substantial risk elevation; fibroid location should not inform clinical reassurance or modify surveillance strategies. Women with fibroid history may benefit from enhanced antenatal surveillance, including close blood pressure monitoring and patient education regarding preeclampsia symptoms.
Future research should focus on elucidating mechanisms and developing improved screening and prevention strategies in this population. Fibroids may reflect an underlying systemic vascular phenotype that predisposes affected individuals to HDP, rather than acting as an isolated uterine pathology.[16,21,24,25] Prospective studies incorporating vascular and biomarker profiling are needed to determine whether these pathways are mechanistically operative or reflect shared upstream determinants. Imaging-based cohorts should examine whether quantitative fibroid burden measures improve risk stratification and whether these characteristics modify the relationship between location and HDP outcomes. Intervention studies testing whether preconception vascular optimization or other targeted strategies reduce fibroid-associated HDP risk would provide critical mechanistic and clinical insights.
These findings should be interpreted in light of the study’s strengths and limitations. This study represents the largest analysis of uterine fibroids and HDP to date, leveraging a propensity score-matched cohort from over 100 US healthcare organizations. The three-way comparison design isolated the independent contribution of myomectomy to HDP risk, and stratification by fibroid location represents the first adequately powered analysis of anatomical location as a modifier of HDP risk. As with all claims-based analyses, findings depend on the accuracy of diagnostic and procedural coding across participating institutions. The reliance on ICD-10 codes for fibroid location precluded assessment of fibroid size, number, total uterine volume, and precise anatomical relationship to the placental implantation site, characteristics that may independently influence HDP risk. Data on medical treatment for fibroids (e.g., GnRH agonists, progestins) were not systematically available in TriNetX. The dataset also lacked specific coding for parity and gravidity, which could not be included as propensity score matching variables. Although chronic hypertension was included as a matching variable, blood pressure recorded at the first prenatal visit could not be isolated as a discrete, patient-level variable for inclusion in the propensity score model. Cohort-level mean systolic and diastolic blood pressure recorded during the baseline period were closely comparable between matched groups across all three comparisons, supporting adequate baseline vascular balance on a characteristic that was not itself matched. In addition, residual confounding from unmeasured clinical and behavioral factors may persist, including dietary factors such as high processed red meat intake, low fruit and vegetable consumption, and low vitamin D—recognized risk factors for both uterine fibroids and hypertensive disorders of pregnancy—which could not be captured or adjusted for within the TriNetX platform.
Conclusions
Uterine fibroids are associated with increased risk of hypertensive disorders of pregnancy, with risk persisting regardless of myomectomy history or fibroid anatomical location. Given the high prevalence of uterine fibroids among individuals of reproductive age, fibroid status should be incorporated into preconception and prenatal risk stratification for HDP. Future research elucidating shared vascular mechanisms is needed to inform targeted screening and prevention strategies and improve maternal outcomes.
Supplementary Material
Uterine fibroids are linked to increased hypertensive disorders of pregnancy risk
Surgical removal of fibroids does not reduce hypertensive disorder risk
Hypertensive pregnancy risk is elevated regardless of fibroid location
Subserosal fibroids carry the same hypertensive risk as cavity-distorting fibroids
Fibroids may signal vascular dysfunction rather than act through mechanical effects
Funding Statement:
This work was supported, in part, by National Institutes of Health grant R01HD094380 and R01HD111243 to Mostafa A. Borahay, MD, PhD.
Footnotes
Declaration of interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Declaration of Interest Statement
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Data Availability Statement:
The data that supported the findings of this study are available through the TriNetX federated electronic health record research platform. Access to TriNetX requires an institutional agreement and is subject to data use restrictions. Requests for access may be directed to TriNetX (www.trinetx.com).
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Associated Data
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Supplementary Materials
Data Availability Statement
The data that supported the findings of this study are available through the TriNetX federated electronic health record research platform. Access to TriNetX requires an institutional agreement and is subject to data use restrictions. Requests for access may be directed to TriNetX (www.trinetx.com).