Association and post-iliac vein stenting symptom improvement of postural orthostatic tachycardia syndrome and orthostatic intolerance with pelvic venous disorders: two retrospective studies

Summary

Background

Patients with Postural Orthostatic Tachycardia Syndrome (POTS) and Orthostatic Intolerance (OI) commonly present with symptoms suggestive of Pelvic Venous Disorders (PeVD). The presence of PeVD may contribute to orthostatic symptoms in these patients due to venous obstruction with stasis and pooling. Iliac vein compression, a PeVD, has historically been treated with iliac venous stenting. The authors hypothesize that patients with POTS frequently have findings of PeVD, that venous outflow obstruction from iliac vein compression exacerbates POTS/OI symptomatology, and that treating PeVD improves POTS/OI symptoms.

Methods

This paper reports results from two studies at two different institutions with a partially overlapping patient population. The first was a retrospective cross-sectional observational study of patients with POTS/OI who presented to Emory University Cardiology (Atlanta, GA, USA) from October 2019 to June 2023. We aimed to evaluate the prevalence of concurrent POTS/OI and PeVD using screening pelvic venous ultrasound, MR and/or CT, compared to venogram with intravascular ultrasound (IVUS). We secondarily evaluated the efficacy of each imaging modality in screening accuracy for PeVD. The second study was a retrospective review of medical records for 271 female patients with POTS/OI who received treatment of PeVD with iliac vein stenting from June 2019 to November 2024 at Minimally Invasive Procedure Specialists (Highlands Ranch, CO). The primary objective of this study was to explore quality of life (QoL) outcomes in female patients with POTS/OI before and after treatment. The secondary objective was to record the prevalence of associated pelvic pain, systemic symptoms, and response to therapy in this population.

Findings

In the first cohort, 129 patients (84% cis female) with a diagnosis of POTS/OI and symptoms of PeVD were assessed by standard imaging for venous pathology. 107 patients (83%) had confirmed pelvic venous compression (iliac vein, renal vein, or both) or pelvic venous congestion on imaging with at least one screening modality. All screening modalities were relatively insensitive in detecting iliac venous compression compared with venography and IVUS. In the second cohort, following iliac vein stenting, significant improvements were seen in Orthostatic Hypotension Questionnaire (OHQ) composite scores at three months (p < 0·001) and at 12 months (p < 0·001). The OHQ Symptom Assessment (OHSA) and Daily Activities Scale (OHDAS) subscores, International Pelvic Pain Society (IPPS) score, Pelvic Congestion Syndrome (PCS) score, Pelvic Pain and Urgency/Frequency Symptom Scale (PUF) score, and Ancillary symptom score all demonstrated statistically significant decreases at three months that persisted at 12 months (all p < 0·001) as well.

Interpretation

The high prevalence of PeVD in POTS/OI patients suggests an association between the two diagnoses. In the absence of expert clinical review, screening with US, CT, and MR may not be sufficient to rule out PeVD. Significant improvements were seen in QoL in patients with POTS/OI and PeVD who underwent iliac vein stenting. These results call for additional trials to examine the clinical and hemodynamic effects of venous stenting on POTS/OI symptomatology and associated systemic symptoms, including pelvic pain.

Funding

These studies received no funding.

Research in context.

Evidence before this study

We searched PubMed for the terms “postural orthostatic tachycardia syndrome” or “orthostatic intolerance” and “May Thurner” or “pelvic vein,” which returned 8 results. While there is no known direct etiological link between postural orthostatic tachycardia syndrome (POTS)/orthostatic intolerance (OI) and pelvic venous disorders (PeVD) such as left common iliac vein (LCIV) compression, a 2021 study by Knuttinen et al. showed that patients with POTS were more likely to have LCIV compression compared to age-matched control patients. Fudim et al. proposed in 2021 that POTS/OI and PeVD may be mechanistically linked through preload failure. Another study by Smith et al., in 2022 found that patients with pelvic venous disease were more likely to report symptoms of POTS, such as dizziness and orthostatic intolerance, compared to the general population. A recent case series of two patients by Ormiston et al., in 2022 demonstrated improvements in POTS symptoms following LCIV stenting. A case study by Pelling et al. and case series by McGeoch et al., both in 2024, described improvement in POTS symptoms after treatment for LCIV compression and veinous insufficiency, respectively. Preliminary results from a prospective multi-center trial by Knuttinen et al., in 2024 show patients with chronic pelvic pain who received LCIV stenting saw significant improvement in POTS/OI symptoms as well as pelvic pain. Two studies by Smith et al., in 2024 and 2025 of patients treated for different types of PeVD showed improvement in POTS/OI and pelvic symptoms.

Added value of this study

In the first study, we demonstrate that many patients with POTS/OI are more likely to have imaging findings of PeVD in comparison to the general population. Additionally, we have identified the frequency of various symptoms in POTS/OI patients that overlap with PeVD and we discuss the validity of various imaging modalities in the diagnosis of PeVD. In the second study, we demonstrate that patients with both POTS/OI and LCIV compression who underwent LCIV stenting reported improvements in POTS/OI symptoms as well as pelvic and ancillary symptoms.

Implications of all the available evidence

Clarifying the relationship between POTS/OI and PeVD may help identify therapeutic targets for a condition that is typically thought to be incurable. Identifying target symptoms in patients with POTS/OI may increase screening with imaging for PeVD and consequent referral for treatment. When patients with both POTS/OI symptoms and LCIV compression receive LCIV stents, POTS/OI symptoms improve. This indicates that LCIV compression may be a contributing mechanism in POTS/OI and that LCIV stenting could be an effective treatment for this condition.

Introduction

Postural Orthostatic Tachycardia Syndrome (POTS) is a heterogeneous clinical disorder that is defined as orthostatic intolerance (OI) associated with a heart rate increase of 30 beats per minute (bpm) (>40 bpm for adolescents) or a rate that exceeds 120 bpm within the first 10 min of standing.^1,2 An estimated 500,000 to three million Americans suffer from this disorder, mainly affecting women of childbearing age with a 5:1 female-to-male predominance.^1,3 Patients commonly present with complaints of palpitations, fatigue, nausea, “brain fog,” lightheadedness, exercise intolerance, tremulousness, and syncope or near syncope, among other symptoms.⁴ POTS is considered a debilitating condition with affected patients having quality of life (QoL) outcomes similar to those seen in patients with congestive heart failure and chronic obstructive pulmonary disease.⁵ Current treatment options for POTS/OI are limited, with regimens focusing on intravascular volume maintenance, prescribed medications utilized to control heart rate and/or blood pressure, compression stockings, and lifestyle changes.²

Pelvic venous disorders (PeVD) is a term that has largely replaced pelvic congestion syndrome as it encompasses all causes of pelvic venous diseases. The main contributors are left common iliac vein (LCIV) compression (also known as May-Thurner Syndrome), left renal vein compression (also known as nutcracker syndrome), gonadal venous reflux with para-ovarian varices (previously known as pelvic congestion syndrome), and varicose veins in the deep pelvic floor. Non-thrombotic iliac vein compression most commonly occurs when the LCIV is compressed between the right common iliac artery and lumbar spine. The most common indications for treatment have been left lower extremity (LLE) iliofemoral deep vein thrombosis (DVT) or LLE swelling, and placement of a stent in the LCIV has been shown to be safe and effective.⁶ Early studies suggest that iliac vein compression may be a more powerful contributor to pelvic symptoms than reflux disease.7, 8, 9, 10, 11 For purposes of this paper, iliac vein or left renal vein compression was considered positive for PeVD with or without accompanying gonadal vein abnormalities or pelvic varices.

Iliac vein compression as an etiology for POTS is a newer association that has not been formally studied in larger populations of patients. In 2021, Knuttinen and colleagues showed that when blinded radiologists interpreted computed tomography (CT) images of pelvic veins in women with POTS versus age-matched renal donor controls, LCIV compression was found in 69% of POTS patients, compared to 40% in the control women.¹² Fudim et al. proposed that POTS/OI may have a link to PeVD through preload failure.¹³ More recently, a case series described improvements in POTS symptoms in two patients aged 16 and 24 years old following LCIV stenting for correction of iliac vein compression, further lending credence to iliac vein stenting as a significant therapeutic option for individuals experiencing POTS-related symptoms.¹⁴ A case study and case series in 2024 described additional patients who reported improvement in POTS symptoms following venous interventions.^15,16 Smith et al. found that, when surveyed, 63% of patients with diagnosed PeVD have symptoms of dizziness and OI compared to 1% in the general population,¹⁷ and that after treatment for PeVD, which included iliac vein stenting in 89% of cases, OI symptoms improved.¹⁸

In this paper, we explore the contribution of PeVD to both POTS/OI and pelvic symptoms, given the high prevalence of these seemingly unrelated symptom complexes occurring simultaneously in many patients. We report results from two studies, one evaluating the issue from the standpoint of patients referred to a cardiologist for POTS/OI to determine the prevalence of symptoms and anatomy of PeVD in this population, as well as the efficacy of screening modalities. The second examines a similar population more often referred for pelvic pain, a subset of whom also suffer from POTS/OI. In this cohort, we examine the efficacy of iliac vein stenting for control of both POTS and associated pelvic pain and systemic symptoms.

Patients referred to the Emory Women's Heart Center who also described symptoms of PeVD were evaluated with standard screening ultrasound (US), computed tomography (CT) and/or magnetic resonance imaging (MRI) studies. We secondarily evaluate the efficacy of each imaging modality in screening accuracy for PeVD compared with the gold standard venogram with intravascular ultrasound (IVUS).

At Minimally Invasive Procedure Specialists (MIPS), we performed a retrospective review of patients with POTS/OI using QoL surveys before and after treatment with LCIV stenting. We also evaluated QoL surveys performed to assess pelvic pain and other associated symptoms in this patient population and reviewed the patient population to determine the prevalence of commonly reported comorbid conditions.

Methods

Emory University cohort

Study participants

This is a retrospective cross sectional observational study of patients with a formal diagnosis of POTS or suspected POTS who presented to Emory University (Atlanta, GA, USA) from October 2019 to June 2023. Baseline demographics, medical history, symptoms, and imaging results were collected via electronic medical record review and patient surveys. Adult patients were enrolled in the cohort if they were diagnosed with POTS or had non-POTS OI symptoms evaluated by our clinic or documented by a prior clinician and they had a complete PeVD workup. All patients provided electronic informed consent for participation in this study. This study was approved by the Emory University Institutional Review Board (STUDY00005587).

Symptom definitions and surveys

A diagnosis of POTS required meeting the formal criteria on a head-up tilt table test (Supplemental Table S1).¹⁹ Patients with a clinical presentation suggestive of POTS who did not meet the orthostatic heart rate criteria or did not have a tilt table test will be referred to in this study as the “non-POTS OI” patient group. These patients include those who were diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), long COVID-19, post-viral fatigue syndrome, inappropriate sinus tachycardia, or autonomic dysfunction/dysautonomia.

Patient symptoms were evaluated using standardized assessments, including the Orthostatic Hypotension Questionnaire (OHQ), International Pelvic Pain Society (IPPS), and Pelvic Pain and Urinary Urgency Frequency (PUF) surveys. The OHQ has been validated as a reliable and accurate assessment of OI/hypotension.²⁰ The IPPS was developed by the International Pelvic Pain Society as a standardized method for evaluating symptoms of chronic pelvic pain relating to menstruation, sexual activity, and bodily pain.²¹ The PUF survey has been determined to be a reliable measurement of interstitial cystitis (IC) symptoms experienced during urination and sexual activity.^22,23 On all surveys, higher scores positively correlate with disease severity.

Imaging modalities

Patients formally diagnosed with POTS or non-POTS OI symptoms were referred for PeVD assessment via vascular ultrasound of the inferior vena cava and iliac veins (pelvic US), magnetic resonance angiography or venography of the abdomen and pelvis (MRA/MRV), and/or computed tomography angiography or venography of the abdomen and pelvis (CTA/CTV) at general imaging facilities. Eighty-two patients went on to be further assessed via pelvic venogram with IVUS, which is considered the gold standard.^8,24, 25, 26 As all imaging was performed by standard of care, screening modality varied by patient based on availability, health insurance coverage, and safety considerations.

Study objectives

The primary objective of the study was to assess the prevalence of symptoms and imaging signs of PeVD in patients with POTS and non-POTS OI symptoms. The secondary objective was to measure the diagnostic utility of standard non-invasive imaging techniques compared to pelvic venogram with IVUS in patients who underwent further assessment.

Statistical analysis

Baseline characteristics and symptoms are reported as number (%) for categorical variables and mean ± standard deviation for continuous variables. Group characteristics were compared using chi-square tests for categorical variables and two-sample t-tests for continuous variables. A p-value <0·05 was considered statistically significant. Statistical analysis was performed with Python 3·13·5 and SciPy 1·15·3.

MIPS cohort

Study participants and procedures

A retrospective review of patient medical records was conducted for 1046 female patients who received iliac vein stents at MIPS from June 2019 to November 2024. After excluding patients with prior DVT in the iliac venous system or who were non-ambulatory for reasons other than POTS/OI, 271 patients demonstrated an Orthostatic Hypotension Questionnaire (OHQ) composite score ≥3. This threshold was chosen because in a previous study of patients with POTS, the 95% confidence interval of the mean OHQ composite score of patients with POTS gave a range of 3·00 to 9·72.²⁷ Patient demographics and medical history were extracted from the electronic medical record system. Scores on QoL assessments completed during pre-procedural consultations and post-procedural follow-up visits were also collected. AdventHealth institutional review board reviewed the study (reference number 2139645) and approved a waiver of informed consent due to the secondary use of records collected for the purposes of healthcare operations. All study procedures were conducted in accordance with the ethical standards set forth by AdventHealth.

Study objectives

The primary objective of this study was to track changes in symptoms of OI and chronic pelvic pain (CPP) before and after iliac vein stenting through QoL surveys in patients with POTS/OI. Secondary objectives included reporting the prevalance of comorbid conditions, as well as the laterality of reported lower extremity pain, swelling, and paresthesia.

Statistical analyses

A repeated measures ANOVA was performed to analyze QoL scores before stenting and at three- and 12-month follow-up visits. When ANOVA showed significant group difference, post-hoc pair-wise t-tests were performed using Bonferroni correction. Descriptive statistics were utilized to analyze demographics and baseline characteristics. All statistics were run as complete case analyses. A p-value <0·05 was considered statistically significant. All statistical analyses were performed utilizing R version 4·5·1 with the tidyverse and rstatix libraries.

Patients were treated with LCIV stent placement if they had symptoms of PeVD, screening imaging suggested LCIV compression, and IVUS showed a >50% reduction in the cross-sectional area of the LCIV with or without dilated sacral venous plexus, ascending lumbar, epidural veins, or cross pelvic collaterals thought to be related to outflow obstruction from iliac vein compression.²⁸

Standardized surveys were given to all MIPS patients before and after their stenting procedures to monitor symptoms. These included the OHQ, IPPS, PUF, Pelvic Congestion Syndrome (PCS), ancillary symptom survey, and Patient Global Impression of Change (PGIC), the latter given only after treatment. A structured ancillary symptom survey adapted from the instrument developed by Smith and colleagues and a PCS survey were utilized to determine the frequency of comorbid conditions.¹⁷

Role of the funding source

There was no funding source for these studies.

Results

Emory University cohort

Study population and baseline clinical characteristics

A total of 287 adult patients with a diagnosis of POTS or non-POTS OI symptoms were asked to participate in this study. 154 patients consented to participate and were screened for symptoms and PeVD. Twenty-five patients were excluded from analysis due to incomplete work up with pending imaging results. The remaining 129 patients were assessed for PeVD and symptomatology (Fig. 1). Symptom differences between patients categorized as POTS versus non-POTS OI are described in Supplemental Table S2. Notably, pelvic symptoms and PeVD presence did not differ significantly between those with a formal diagnosis of POTS versus those without.

Fig. 1.

Consort Diagram. Abbreviations: PeVD—pelvic venous disorder; IVUS—intravascular ultrasound.

Demographics of this cohort are described in Table 1. The mean age was 36·2 ± 12·1 years (range: 18–70). Patients were predominantly cis female (84%) and white (74%). Among OI evaluations, 84 (65%) patients had a formal diagnosis of POTS, 58 of whom were diagnosed prior to initial presentation at the clinic, and 45 (35%) patients did not meet the formal diagnosis for POTS in clinic (“non-POTS OI” group) but had presentations strongly suggestive of POTS. The average supine heart rate in clinic was 80·6 bpm, the average sitting heart rate was 85·8 bpm, and the average standing heart rate was 101·9 bpm.

Table 1.

Demographics and baseline characteristics.

Characteristic	Total N = 129
Age (years)	36·2 ± 12·1
BMI (kg/m2)	26·9 ± 7·0
Gender	–
Cis Female	109 (84%)
Cis Male	10 (8%)
Gender Queer/Gender Nonconforming	2 (2%)
Nonbinary	4 (3%)
Transmasculine	1 (1%)
Other	3 (2%)
Assigned female at birth	117 (91%)
Race/Ethnicity	–
White	95 (74%)
Black	5 (4%)
Latino	2 (2%)
Asian	3 (2%)
Other/Multiple Racial or Ethnic Groups	13 (10%)
Unanswered	11 (9%)
Orthostatic Intolerance Evaluation	–
Diagnosis of POTS	84 (65%)
POTS-like presentation	45 (35%)
Previous POTS diagnosis	58 (45%)
Previously diagnosed with dysautonomia/orthostatic intolerance	17 (13%)
Orthostatic Vital Signs	–
Supine HR (bpm)a	80·6 ± 14·8
Sitting HR (bpm)	85·8 ± 15·0
Standing HR (bpm)a	101·9 ± 18·4
Supine SBP (mmHg)	117·9 ± 12·4
Supine DBP (mmHg)	72·4 ± 9·1
Sitting SBP (mmHg)	118·1 ± 14·0
Sitting DBP (mmHg)	74·3 ± 10·2
Standing SBP (mmHg)	118·2 ± 13·3
Standing DBP (mmHg)	74·4 ± 9·8
Comorbid Conditions	–
History of DVT/PE	6 (5%)
PCOS	26 (20%)
MCAS/Suspected MCAS	94 (73%)
Ehlers-Danlos Syndrome	24 (19%)
Symptom Association with COVID-19 infection	–
Symptoms after COVID-19	45 (35%)
Symptoms exacerbated by COVID-19	21 (16%)
No effect of COVID-19 on symptoms or no infection documented	62 (48%)

Abbreviations: BMI—body mass index; bpm—beats per minute; DBP—diastolic blood pressure; DVT—deep venous thrombosis; HR—heart rate; MCAS—mast cell activation syndrome; PCOS—polycystic ovarian syndrome; PE—pulmonary embolism; POTS—postural orthostatic tachycardia syndrome; SBP—systolic blood pressure.

^aMissing >50% of data for cohort. For continuous variables, mean ± standard deviation is reported. For categorical variables, n (%) is reported.

Symptoms reported in the final cohort are described in Table 2. Pelvic pain or heaviness was reported by 96 patients (74%). Lower extremity symptoms were reported, with 83 patients (64%) reporting pain and 80 patients (62%) reporting edema. Over half of the cohort reported urinary (57%) or menstrual (61%) symptoms.

Table 2.

Frequency of presenting symptoms in patients with postural orthostatic tachycardia syndrome/orthostatic intolerance.

Symptom	Total cohort (N = 135)
Tachycardia	118 (91%)
Dizziness	110 (85%)
Pre-Syncope	33 (26%)
Syncope	46 (36%)
Brain fog	76 (59%)
Headache or Migraine	99 (77%)
Lower gastrointestinal symptoms	92 (71%)
Upper gastrointestinal symptoms	89 (69%)
Lower back pain	43 (33%)
Lower extremity discoloration	40 (31%)
Lower extremity pain	83 (64%)
Lower extremity edema	80 (62%)
Varicose veins	33 (26%)
Dysmenorrhea/menorrhagia (N = 117)	71 (61%)
Pelvic pain or heaviness	96 (74%)
Urinary symptoms	73 (57%)
Hypermobility NOS	41 (32%)
Survey Responders	–
OHQ Survey Score (N = 116)	43·8 ± 22·2
IPPS Survey Score (N = 99)	55·2 ± 30·2
PUF Survey Score (N = 90)	9·7 ± 4·1
Score ≥10	42 (33%)
Score <10	118 (91%)

Abbreviations: IPPS—International Pelvic Pain Society Survey; MCAS—mast cell activation syndrome; NOS—not otherwise specified; OHQ—Orthostatic Hypotension Questionnaire; PUF—Pelvic Pain and Urinary Urgency Frequency Survey.

For continuous variables, mean ± standard deviation is reported. For categorical variables, n (%) is reported.

Minium to maximum scores of each survey: OHQ: 0–50; IPPS: 0–160; PUF: 0–35; a score ≥10 has a 74% chance or more of interstitial cystitis (Parsons et al., 2002).

Imaging outcomes

107 patients (83%) had confirmed PeVD with at least one modality (Table 3, Fig. 1). Findings confirming PeVD on these screening exams included iliac vein compression, left renal vein compression, and dilated presacral, paralumbar, and epidural veins. Patients were considered positive for PeVD on noninvasive imaging if the initial interpreting radiologist mentioned these findings and/or if a second positive interpretation was provided by an interventional radiologist. Screening findings were deemed positive for compression regardless of the degree of stenosis mentioned on imaging because the reading radiologists generally did not quantify the degree of compression. In comparison with the gold standard venogram/IVUS, there were no false positive findings on any screening modality, and thus it is likely that radiologists’ current tendency is to under-call PeVD, meaning that, when mentioned at all, compression is likely >50% in most cases (Fig. 1).

Table 3.

Diagnosis of pelvic venous disorders in patients with POTS/OI across multiple imaging modalities.

Modality	n patients who underwent test	n (%) patients with positive findings
Pelvic US	119	55 (46)
CT	31	16 (52)
MR	48	32 (67)
Venogram/IVUS	81	80 (99)
Any	129	107 (83)

Abbreviations: CT—computed tomography; IVUS—intravascular ultrasound; MR—magnetic resonance; US—ultrasound.

Pelvic US was performed on 119 patients, with 55 patients (46%) who had findings of PeVD. CT was performed in 31 patients, with 16 patients (52%) revealing positive findings for PeVD. MRI was performed on 48 patients, with 32 patients (67%) revealing positive findings for PeVD. Venogram/IVUS was performed in 81 patients, with 80 patients (99%) revealing positive findings for PeVD. In the subsets of each screening modality group for which there was a corresponding venogram/IVUS performed, we found sensitivity rates of 53%, 50%, and 72% for pelvic US, CT, and MRI, respectively (Table 4).

Table 4.

Sensitivity of pelvic venous disorder screening modalities compared with gold standard Venogram/IVUS.

Modality	n	True positives	True negatives	False positives	False negatives	Sensitivity
Pelvic US	74	39	1	0	34	53%
CT	23	11	1	0	11	50%
MR	30	21	1	0	8	72%

Abbreviations: CT—computed tomography; IVUS—ntravascular ultrasound; MR—magnetic resonance; US—ultrasound.

MIPS cohort

Baseline clinical characteristics and symptoms

The study cohort was comprised of 271 female participants with a mean age of 36·20 (SD = 12·74, range: 15–79) years, all of whom presented with POTS/OI. Mean LCIV stenosis by cross-sectional area in the study population was 78% (SD = 9%). The cohort exhibited a variety of comorbid conditions and symptoms, as described in Table 5. This comprehensive clinical characterization of patients with POTS/OI provides a robust foundation for understanding the prevalence of comorbid conditions and symptoms in this population. Notably, listed here from most to least prevalent, patients reported pelvic pain/heaviness, lower gastrointestinal (GI) symptoms, lower back pain, urinary frequency/urgency/dysuria, presyncope/syncope, dyspareunia, dysmenorrhea, anxiety, migraines and headaches, palpitations, depression, temporomandibular joint disorder (TMJ), upper GI symptoms, Ehlers-Danlos Syndrome (EDS)/hypermobility, irritable bowel syndrome (IBS), mast cell activation syndrome (MCAS), and chronic fatigue.

Table 5.

Frequency of symptoms/comorbidities in 271 patients with significant left iliac vein compression and POTS/OI.

	Frequency	Percent
Pelvic Pain/Heaviness	260	96
Lower GI Symptoms	259	96
Lower Back Pain	254	94
Urinary Frequency/Urgency/Dysuria	250	92
Presyncope/Syncope	244	90
Dyspareunia	213	79
Dysmenorrhea	202	75
Anxiety	196	72
Migraines/Headaches	192	71
Palpitations	188	69
Depression	176	65
TMJ	148	55
Upper GI Symptoms	145	54
EDS/Hypermobility	96	35
IBS	80	30
Mast Cell Activation Syndrome	78	29
Chronic Fatigue	71	26

Abbreviations: GI—gastrointestinal; TMJ—temporomandibular joint disorder; EDS—Ehlers-Danlos syndrome; IBS—irritable bowel syndrome.

Laterality of lower extremity symptoms was also assessed in this cohort (Table 6). Although LCIV compression is commonly associated with LLE symptoms,²⁹ bilateral presentation of lower extremity symptoms in this cohort was more frequent, with 55% of patients reporting bilateral lower extremity pain, 40% reporting bilateral lower extremity swelling, and 19% reporting bilateral lower extremity paresthesia. Unilateral pain in the LLE was present in 13% of patients, swelling of the LLE was seen in 7% of patients, and paresthesia in 6%. Unilateral right lower extremity pain was seen in 3% of patients, swelling of the right lower extremity in 3% of patients, and right lower extremity paresthesia in 1%.

Table 6.

Frequency of lower extremity symptoms in 271 patients with significant left iliac vein compression and POTS/OI.

	Frequency (Percent)
	Bilateral	Unilateral left	Unilateral right
Pain	150 (55)	36 (13)	8 (3)
Swelling	109 (40)	18 (7)	7 (3)
Paresthesia	52 (19)	16 (6)	4 (1)

QoL outcomes

Patients reported statistically significant improvements in symptoms of POTS/OI as assessed through OHQ composite scores reported prior to stenting (mean = 6·24, SD = 1·82) and at three months post-procedure (mean = 4·07, SD = 2·47), p < 0·001 (Fig. 2). This improvement was maintained at 12 months post-stenting (mean = 3·67, SD = 2·53), p < 0·001. Significant differences were also demonstrated in OHQ Symptom Assessment (OHSA) subscores when assessed prior to stenting (mean = 6·27, SD = 1·82), at three months post-procedure (mean = 4·13, SD = 2·53), p < 0·001, and at 12 months post-procedure (mean = 3·81, SD = 2·70), p < 0·001. Similarly, the OHQ Daily Activities Scale (OHDAS) subscores improved between pre-stent (mean = 6·45, SD = 2·34) and three months post-procedure (mean = 3·61, SD = 2·54), p < 0·001, maintained at 12 months post-procedure (mean = 2·62, SD = 1·59), p < 0·001. In the original validation of the OHQ, Kauffman and colleagues found that a change of 0·83 in the OHQ composite score was a minimally important difference to classify treatment response.²⁰ At three months post-procedure, 68% of patients met this responder threshold, and in 35% of patients the OHQ composite score had fallen below 3, indicating a remission in symptoms. At 12 months post-procedure 71% met the response threshold and 44% had a score below 3.

Fig. 2.

Orthostatic Hypotension Questionnaire (OHQ) Composite scores, Orthostatic Hypotension Symptom Assessment (OHSA) subscores, and Orthostatic Hypotension Daily Activities Scale (OHDAS) subscores. Y-axis value represents observed mean. Error bars represent 95% confidence interval. ∗ indicates significant (p < 0·0001) change from pre-stent.

Changes in IPPS scores indicate that patients had improvement in pelvic symptoms from before stenting (mean = 63·7, SD = 29·7) to three months post-procedure (mean = 40·2, SD = 30·5), p < 0·001 which was maintained at twelve months post-procedure (mean = 36·2, SD = 28·3), p < 0·001 (Fig. 3a). Furthermore, there were significant differences in PCS scores when assessed pre-procedure (mean = 31·50, SD = 17·12), at three months post-procedure (mean = 17·15, SD = 15·61), p < 0·001, and at 12 months post-procedure (mean = 13·91, SD = 13·54), p < 0·001 (Fig. 3b).

Fig. 3.

a) International Pelvic Pain Society (IPPS) Scores. b) Pelvic Congestion Syndrome (PCS) scores. c) Pelvic Pain and Urgency/Frequency Patient Symptom Scale (PUF) composite scores, PUF symptom (PUF–S) subscores, and PUF bother (PUF–B) subscores. Y-axis value represents observed mean score. Error bars represent 95% confidence interval. ∗ indicates significant (p < 0·0001) change from pre-stent.

We also found significant improvement in pelvic and urinary symptoms as reported on the PUF survey prior to stenting (mean = 14·42, SD = 6·34), at three months post-procedure (mean = 10·34, SD = 6·28), and at 12 months post-procedure (mean = 9·00, SD = 6·27). This improvement was also seen in the PUF symptom and bother (PUF–S and PUF-B) subscores. The PUF-S subscore changed significantly between pre-procedure (mean = 9·24, SD = 4·18) and three months-post procedure (mean = 6·72, SD = 4·06), p < 0·001, as well as 12 months post-procedure (mean = 5·91, SD = 4·02), p < 0·001. The PUF-B subscore changed significantly between pre-procedure (mean = 5·17, SD = 2·60) and three months-post procedure (mean = 3·62, SD = 2·51), p < 0·001, as well as 12 months post-procedure (mean = 3·03, SD = 2·54), p < 0·001 (Fig. 3c).

Patients reported significant improvement in related systemic symptoms as assessed by our Ancillary Symptoms survey from pre-procedure (mean = 45·96, SD = 24·24) to three months post-procedure (mean = 29·21, SD = 22·47) and maintained at 12 months post-procedure (mean = 26·10, SD = 21·66) (Fig. 4).

Fig. 4.

Ancillary Symptoms scores. Y-axis value represents observed mean. Error bars represent 95% confidence interval. ∗indicates significant (p < 0·0001) change from pre-stent.

Finally, of the 271 patients in the study, 254 completed the PGIC assessment at three months post-procedure and 98 completed the PGIC assessment at 12 months post-procedure. At three months 78% of respondents reported improvement in global symptoms and at 12 months 80% of respondents reported improvement in global symptoms (Fig. 5).

Fig. 5.

Patient Global Impression of Change (PGIC) scores for 254 patients three months after venous stenting and 98 patients twelve months after venous stenting.

Adverse events

Among the 271 participants, there were 15 reported minor adverse events, and no major adverse events related to the stenting procedure. Two patients developed a non-obstructive, asymptomatic thrombus in the iliac stent. Five patients developed thrombus or hematoma at the great saphenous vein access site. Six patients required emergency department visits (without admission) for acute post-procedure pain control or shortness of breath. One patient required hospitalization for acute post-procedure pain control. One patient reported worsening migraines.

Discussion

These studies encompass two of the largest cohorts further characterizing the phenotype and symptoms of POTS/OI patients. In the first study, we identify PeVD as a comorbidity that may also cause or exacerbate cardiac symptoms due to decreased venous blood return to the heart and pelvic venous pooling. The second study demonstrates clinical improvement in both POTS/OI and CPP after iliac venous stenting. The effects were statistically and clinically significant at three months and persisted at 12 months post-procedure. This lends further credence to the possibility that PeVD is a novel contributing mechanism in the pathophysiology of POTS/OI and CPP.

CPP and POTS/OI have in common that many medical specialties have yet to identify definitive causal factors that contribute to the onset and persistence of symptoms. CPP is a common condition that causes significant impairment in lifestyle in women, representing 30% of all referrals to OBGYN offices.³⁰ This pain can consist of constant or intermittent lower abdominal/pelvic pain, dysmenorrhea, dyspareunia, and/or dysuria present for at least six months.³¹ Within the existing gynecologic and broader pain literature, vascular origin pain is not in the differential diagnosis for CPP.^32,33 However, in 2001 Soysal and colleagues reported that 31% of patients who underwent gynecologic workup and were determined to have CPP of unknown origin were later found to have PeVD as their only pathology.³⁴ Daugherty and colleagues found complete or partial resolution of CPP in 19 patients treated with LCIV stenting.⁹ Santoshi and colleagues found that 80% of patients with PeVD had greater than 50% iliac vein compression, and that iliac vein stenting may provide greater relief from CPP than gonadal vein embolization alone.⁷ Lakhanpal and colleagues found that 76% of patients with both iliac vein compression and ovarian vein reflux had complete symptom resolution with iliac stenting alone.⁸ Villalba and Larkin found clinically and statistically significant long-term reduction of CPP in patients who received LCIV stenting, even in patients with residual reflux, with 73% achieving complete remission.¹⁰ Gavrilov and colleagues showed that in patients with both CPP and gonadal reflux, gonadal vein embolization alone did not provide CPP relief but that LCIV stenting was an effective first-line treatment.¹¹ In this MIPS cohort, although we did not select specifically for CPP, we also saw significant reduction in pelvic symptoms as reported on the IPPS, PCS, and PUF surveys after iliac vein stenting (Fig. 3).

It is very difficult to estimate the number of patients in the general population with symptomatic iliac vein compression because, until recently, the only symptoms felt to be attributed to iliac vein compression were LLE pain/swelling and DVT. One 2023 review article estimated that in the general population of women between the ages of 20–50 approximately 15% have PeVD of variable clinical significance.³⁵ Clinical suspicion is key to the diagnosis of PeVD in the POTS/OI population. In our Emory cohort, patients with POTS/OI and PeVD were more likely to present with symptoms of pelvic pain compared to POTS/OI patients without PeVD. In addition to pelvic symptoms, syncope appears to be more prevalent in this population, suggesting that peripheral venous pooling may have a contributory role to this common POTS symptom and should raise suspicion in providers. Patients with PeVD had higher scores on all three symptom surveys (OHQ, IPPS, PUF), indicating worse symptoms at baseline.

Once patients are found to have a reasonable clinical suspicion for PeVD based on presenting symptoms, clinicians must decide the next best imaging techniques to confirm the diagnosis. More than half of the cohort in the Emory study was screened for PeVD using pelvic US. US is widely used as a screening test, as it is time efficient, low risk, and low cost. It does not involve intervention or radiation exposure and is easily accessible at most medical centers. However, ultrasound is highly operator dependent and the rate of detection of PeVD is likely significantly higher in centers with a vascular lab or at gynecologic practices dedicated to specifically evaluating for PeVD with advanced protocols and interpretation.^36,37 Therefore, exams ordered at a general imaging center or university, as in this study, reported as “normal” pelvic US do not necessarily rule out PeVD. In this cohort, pelvic US demonstrated a sensitivity of 53% for iliac venous compression.

CT imaging is low cost and more time efficient compared to MRI. Benefits of CT imaging over US include higher temporal and spatial resolution, multiplanar reformatting, and 3D reconstruction images, which in previous publications was felt to account for better sensitivity.^36,38 Potential drawbacks of CT testing include contrast allergies and radiation exposure. Of the subset of patients who underwent CT in the Emory cohort, the sensitivity was 50%, which was similar to US.

MRI/MRV has a higher sensitivity for detecting PeVD than both US and CT, with a sensitivity of 72% in this cohort. A study of 25 patients by Attia et al. found the sensitivity and specificity of MRV for the detection of reflux to be 75% and 53% for the internal iliac veins.³⁹ MRI can visualize anatomical regions with good morphological evaluation to help diagnose PeVD. Post contrast images allow for visualization/distinction of the vein wall versus the lumen which, when used for diagnostic purposes, can be helpful to get better correlation with IVUS. MR is non-invasive and does not harbor the risk of radiation exposure. Characterization of abnormalities of the uterus, ovaries, and fallopian tubes that can contribute to pelvic pain, disease in the lumbar spine that can contribute to back pain, musculoskeletal abnormalities in the sacroiliac joints and pelvis, and other disease processes such as lymphadenopathy, tumors, compressive lesions, retroperitoneal fibrosis, and radiation change, all of which could lead to vascular compression, are imaged to best advantage on MRI.

While IVUS has traditionally been used in coronary angiography to assess plaque characteristics and stent deployment, it has also been applied to venous pathology, improving the sensitivity of detecting lesions compared to traditional venography.40, 41, 42 In iliac vein obstruction, venogram is performed to identify compression and collateralization, and IVUS can be used subsequently to evaluate the degree of stenosis from external compression and or residual thrombus, and is used to determine the size of the vein for stent selection. This invasive diagnostic test has the benefit of offering the option for real-time therapy in the form of stenting, balloon dilatation, thrombolysis, and thrombectomy compared to non-invasive testing and is considered the true “gold standard” for venous stenosis evaluation.⁴²

Several studies have compared the sensitivity of IVUS to other common imaging modalities to assess PeVD. Müller et al. compared the accuracy of duplex pelvic US, MRV, and multiplanar venography compared to IVUS in detecting obstruction in femoral veins, iliac veins, and the inferior vena cava.⁴³ For non-thrombotic lesions, duplex US had the lowest sensitivity (58%) and specificity (30%) compared to MRV (sensitivity 90%, specificity 40%) and venography (sensitivity: 95%, specificity: 95%). For thrombotic lesions, all three modalities were highly sensitive and specific for lesions in iliac veins, but less so for common femoral veins and the inferior vena cava. Based on the results of the present study, less invasive imaging modalities should be pursued prior to IVUS; however, IVUS should still be performed if there is a high clinical index of suspicion for iliac or renal vein compression.

Once iliac vein compression is suspected in patients with orthostatic symptoms and abdominal/pelvic symptoms, and screening exams have been performed or in the presence of strong clinical suspicion, patients would then go on to receive the gold standard of venography and IVUS to determine whether iliac venous stenting is appropriate. This exam can be performed simultaneously with stenting or in a separate setting.

Our Emory cohort demonstrated a high (83%) prevalence of PeVD amongst POTS/OI patients. This is in concordance with another study that, while limited by small numbers, suggested that the prevalence of LCIV compression in POTS patients is higher than in controls.¹² In our MIPS cohort of patients with both PeVD and POTS/OI, the significant reduction in orthostatic symptoms after PeVD treatment further supports the connection between the two.

Currently published in the literature are several different theories of the pathophysiology of POTS/OI. Patients have often been characterized into three main groups: hyperadrenergic, hypovolemic, and neuropathic POTS. Hyperadrenergic POTS is characterized by orthostatic increases in plasma norepinephrine and blood pressure.⁴⁴ Hypovolemia in POTS is measured through various radioimmunoassays, typically from antecubital venous blood, and is associated with abnormal renin-angiotensin-aldosterone interactions.⁴⁵ This is generally differentiated from neuropathic POTS, which is felt to relate to redistributive central hypovolemia in the upright position as opposed to absolute hypovolemia. This is hypothesized to be due to small fiber neuropathy leading to decreased adrenergic vasoconstriction in the legs or the splanchnic vasculature, causing baroreflex unloading, decreased reflex cardiovagal stimulation, increased reflex sympathetic excitation, and reflex tachycardia.⁴⁶

Iliac vein compression results in impeded venous outflow and reversed blood flow in the internal iliac veins (Fig. 6). This results in elevated venous pressure throughout the pelvis and in some cases the lower extremities, and, conversely, lower central venous pressure.⁴⁷ It is possible that the decreased blood return to the heart or centralized hypovolemia is present in patients with hyperadrenergic POTS and that venous pooling causes the adrenal adrenergic response in order to prevent hypotension and syncope and to shunt blood centrally. Central hypovolemia may also be caused by actual venous obstruction and venous pooling as opposed to isolated contribution from small fiber neuropathy. In both of these settings, stenting the iliac vein to return blood flow to the heart could potentially lead to improved symptoms. In the theory of absolute hypovolemia, it is less clear whether iliac venous stenting would improve postural symptoms.

Fig. 6.

Venogram of patient from the MIPS cohort before and after left common iliac vein (LCIV) stenting. a: Severe iliac vein compression with retrograde flow into the internal iliac, through the presacral plexus and throughout the epidural venous plexus. b: Resolution of diverted flow from the iliac vein through collaterals with return of direct venous drainage through the iliac vein to the inferior vena cava and heart in the same patient following LCIV stenting.

One other mechanism proposed to contribute to postural tachycardia includes a dysregulated baroreceptor response in the carotid arteries.⁴⁸ This may also be linked to the empty right heart theory, and improving central venous return could potentially improve symptoms in these patients as well (Fig. 7).

Fig. 7.

Central Illustration. Association of Postural Orthostatic Tachycardia Syndrome and Orthostatic Intolerance with Pelvic Venous Disorders. Created withBiorender.com. Proposed Pathophysiology Figure adapted from O'Sullivan et al.

Regardless of the cause/effect relationship, decreasing peripheral venous pooling by stenting the iliac vein in this study resulted in the resolution of orthostatic symptoms in 44% of patients and significant clinical improvement in 71% of patients at one-year post-procedure.

The interactions of all these therapies and the interplay of these pathophysiologies may explain why some patients did not respond to iliac venous stenting alone. However, it is possible that residual causes of direct decreased venous return, such as untreated renal vein compression, lower extremity venous insufficiency, or pelvic venous reflux, could also be contributing in those nonresponders. We intend to do a follow-up evaluation to look at what contributory factors may be identified in the nonresponders.

To understand how iliac compression contributes to pelvic pain, we consider the most common collateral venous drainage pathways identified on venography, including the ascending lumbar vein, epidural venous plexus, presacral venous plexus, and retrograde flow into the internal iliac vein.⁴⁷ Direct compression of the nerves within these lumbosacral neurovascular bundles may explain neuralgic pain in the pelvic organs and pelvic floor. Pelvic pain may also be elicited by stretching the nociceptors in the vein wall.⁴⁹

The T10–S4 somatic and autonomic nerves innervate the pelvic floor, bladder, and lower bowel. In the MIPS cohort, 96% of patients reported pelvic pain and heaviness, 96% lower GI symptoms (including bloating, intermittent constipation, and diarrhea), 92% urinary symptoms (including urinary frequency/urgency and dysuria), 79% dyspareunia, and 75% dysmenorrhea.

Our MIPS cohort demonstrates a higher prevalence of bilateral lower extremity pain, with bilateral pain present in 55% of the patients, as opposed to the 13% of patients who reported isolated LLE pain. In fact, 3% reported unilateral right lower extremity pain. It is noteworthy that 17% of these patients reported no lower extremity symptoms. Many vascular specialists withhold treatment in patients with iliac vein compression and an array of symptoms if those symptoms do not include specifically unilateral LLE pain or swelling or prior DVT. Stented patients saw significant clinical improvements in both OI and pelvic pain after stenting, suggesting that iliac venous compression causes many issues other than lower extremity symptoms alone, and stenting should not be excluded as a treatment option for patients with both POTS/OI and CPP in the absence of such symptoms. This is in concordance with Smith and colleagues’ work that showed significant decrease in OHQ, IPPS, and PUF scores after treatment for PeVD and a recent prospective multicenter trial evaluating these QoL surveys before and after iliac vein stenting for CPP that also demonstrated a statistically significant improvement in POTS/OI and pelvic pain at three months that was maintained at 12 months.^18,50

Understanding the most common comorbidities seen in this patient population is essential to developing patient-centered treatment approaches. Multiple conditions, including POTS, ME/CFS, EDS/hypermobility, IBS, IC, TMJ, chronic headaches, and low back pain, have been found to occur at higher rates together and frequently coexist in the presence of CPP and PeVD.^12,51, 52, 53 We found this to be the case in our cohorts as well, with high rates of chronic fatigue, hypermobility, GI symptoms, urinary dysfunction, chronic headaches, and low back pain in both. In particular, we found rates of the EDS/hypermobility to be 51% and 35% in the Emory and MIPS cohorts, respectively. While there is no definitive epidemiological study on the prevalence of hypermobility, rates are thought to be between 10 and 30% of the general adult population.⁵⁴ Previous studies have shown that patients with EDS/hypermobility undergoing endovascular procedures have outcomes similar to those without.^18,55 Given the high collagen content in vein walls, patients with hypermobile collagen and or extracellular matrix defects may be more susceptible to vascular compression and the effects of elevated venous pressures, and future study in this population is warranted.

The Emory cohort study was cross-sectional in nature, and so the temporal relationship between PeVD and POTS is not entirely clear. Future longitudinal studies are needed to establish the timeline of POTS signs and symptoms before and after PeVD intervention. This study was also prone to selection bias, given that most patients were referred for their OI symptoms. Additionally, because our clinic is familiar with this patient presentation, we had a lower threshold to pursue imaging for these patients compared to other institutions. Many of these patients were also on medication therapy for OI before presentation, confounding baseline vital measures. Some patients had received a formal diagnosis of POTS by an outside cardiologist before presenting to our institution and were not reassessed for diagnosis.

The MIPS cohort study was a retrospective chart review, which limits the data available for analysis. The availability of follow-up data could be related to patient outcomes, which would introduce bias into our complete case analysis. All outcomes measures were self-reported, increasing the odds of response error and recall bias. As MIPS providers do not manage POTS/OI directly, previous and concomitant treatments may not be documented and could not be controlled for. Together, these studies strengthen the association between POTS/OI and PeVD. Treating iliac vein compression demonstrated significant symptom improvement in the majority of patients suffering from these conditions.

Certainly, further studies, including a prospective randomized sham trial, would be helpful in excluding placebo effect as a contributing factor to these findings. Additionally, further studies need to be performed evaluating the pathophysiologic mechanisms behind the resolution of POTS/OI symptoms, including evaluation of many parameters included in prior studies characterizing POT/OI. EMG and nerve conduction studies before and after stenting may determine if nerve root compression is a contributing factor to the pathophysiology of pain and dysautonomia in these patients as well. In an area of medicine that is poorly understood with few effective treatment options and limited scientific data, PeVD may be a promising and treatable underlying condition for POTS/OI patients.

Contributors

Elizabeth Brooke Spencer, MD–PI for IRB for MIPS cohort, literature search, study design, data interpretation, writing.

Malika Elhage Hassan–Investigation, data curation, formal analysis, writing -original draft, visualization, accessed and verified the data.

Junmi Saikia, MD, PhD–literature search, study design, data collection, data analysis, writing.

Deeksha Ajeya–literature search, study design, data collection, data analysis, data interpretation, writing.

Raquel Phillips–literature search, data collection, data analysis, figures, data interpretation, writing, accessed and verified the data.

Rebecca Steinberg–data curation, formal analysis, writing.

Leenah Abojaib–introduction writing (original draft), Fig. 1 (Consort Diagram) design.

Kristina Bortfeld–Data curation and writing (review & editing).

Siya Thadani–Data curation, formal analysis, and writing (review & editing).

Alyssa Bernstein–writing, review, and editing.

Catherine McGeoch -Data curation and writing (review & editing).

Brandon Davis–Data curation and writing (review & editing).

Mariana Garcia–Data curation and writing (review & editing).

Zakaria Almuwaqqat–Data interpretation and critical review.

Charles Gilliland–Data interpretation and critical review.

Alexis Cutchins, MD–PI for IRB for Emory cohort, supervision of co-authors, review and editing of manuscript, review of data collection and data analysis, instigator of research.

Data sharing statement

Individual participant data is not available for sharing.

Declaration of interests

EBS's institution has received payments for grants and contracts from Medtronic and Boston Scientific. EBS has received consulting fees from Medtronic, Philips, and Boston Scientific. RP's institution has received payments for grants and contracts from Medtronic. CM receives funding via an NIH training grant. All other authors declare no conflicts of interest.