Long-term follow-up for the treatment of symptomatic pelvic venous insufficiency secondary to combined iliac vein stenosis and ovarian vein reflux treated with iliac vein stenting alone.

Conception and design: AT, GL, LS, RK, SL, PP Analysis and interpretation: AT, LS, PP Data collection: AT, LS Writing the article: AT, LS, PP Critical revision of the article: AT, GL, LS, RK, SL, PP Final approval of the article: AT, GL, LS, RK, SL, PP Statistical analysis: AT, LS, PP Obtained funding: RK, SL, PP Overall responsibility: PP

This study was funded by a grant from the Lakhanpal Vein Foundation .

We retrospectively reviewed prospectively collected data from January 2018 to January 2023, from our Office of the National Coordinator for Health Information Technology certified electronic medical record (Nextgen Healthcare Information Systems, Irvine, CA) at the Center for Vascular Medicine (CVM). Institutional review board approval for the investigation was obtained (Integ Review IRB, Austin, TX). Informed consent was not required as per the institutional review board. Women with PVI secondary to combined IVS and OVR were included in the study. It is our protocol at CVM that all patients receive a thorough evaluation by a gynecologist for non-venous-related causes of chronic pelvic pain before considering interventions for symptomatic PVI. Once other pelvic pain causes were ruled out, a CVM venous specialist evaluates patients for the presence of symptomatic PVI. A venous specialist is defined as a physician who dedicates their practice to the care of patients with venous disease. At CVM, this cohort consists of board-certified physicians in vascular surgery, cardiology, gynecology and cardiothoracic surgery. We also use advanced practice nurses and physician assistants to optimize the intake process. All patients with a negative gynecological assessment for chronic pelvic pain, a history of pelvic pain, dyspareunia, postcoital pain, urinary frequency, flank pain, abdominal bloating, and/or clinical evidence of lower extremity pelvic escape veins, were evaluated with a transabdominal ultrasound (TAU) examination. Patients with clinical symptoms and positive TAU findings were offered, diagnostic venography, intravascular ultrasound examination and possible iliac vein stenting. Our TAU protocol has been published previously. 23 , 24 Briefly, all patients were fasted after midnight and given simethicone to minimize the presence of intra-abdominal gas the morning of the imaging assessment. Ultrasound examinations were performed using either a Samsung HS70 CA1-7A with a curvilinear probe or a GE S8 C1-5 with a curvilinear probe (Samsung, Seoul, South Korea; General Electric, Boston, MA). The angle of insonation was set at 60°, and the sample volume was parallel to the flow channel. Patients were placed in a supine and reverse Trendelenburg position for diameter measurements. Diameter measurements of the common femoral veins, external iliac veins, common iliac veins, ovarian veins and inferior vena cava (IVC) were obtained after obtaining longitudinal images. Diameter measurements were obtained by drawing a perpendicular line with Doppler calipers where the vein walls appeared parallel in the prestenotic and stenotic portions of the vein. Variable vein diameters due to body habitus were accounted for by using the patient's ipsilateral common femoral vein diameter and applying the following formula: Stenosis = (1 − ([Vein Diameter stenosis mm]/[Ipsilateral common femoral vein diameter mm])) × 100. A significant stenosis was defined as a normalized diameter of ≤5 mm. 23 Duplex ultrasound examination was performed before the intervention; 1 week after the intervention; 3, 6, 12, 18, and 24 months after the intervention; and yearly thereafter. Medical/surgical histories, presenting signs and symptoms, preintervention, and 1-, 3-, 6-, 12-, 18-, 24-, and 36-month visual analog scale (VAS) pain scores, stent type, diameter, length, location, ovarian vein diameter, presence of a pelvic reservoir, and types of reinterventions were all evaluated. All treated women underwent a diagnostic venogram, which consisted of an anteroposterior view of the bilateral iliac veins, IVC, left renal vein, left ovarian veins, and any pelvic veins. Balloon occlusion venography of the internal iliac veins and interrogation of the right ovarian vein was not performed. All patients had a prestenting and poststenting intravascular ultrasound examination for the identification of an area-reducing lesion of the iliac veins and confirmation of good wall apposition and appropriate stent expansion. If a residual stenosis required postdeployment venoplasty, a completion intravascular ultrasound examination was performed to ensure proper expansion of the residual stenosis. A pelvic reservoir was defined as the presence of cross-pelvic collaterals, the presence of at least three unilateral and/or bilateral pelvic segments that communicated with either the internal iliac vein, and/or ovarian veins. All venograms were reviewed by one of the senior authors (G.L.) for accuracy. Antiplatelet therapy after stent implantation was not used. Anticoagulation with a factor Xa inhibitor for 90 days after stent implantation is used at the discretion of the treating physician. Indications for extending anticoagulation past 90 days is the presence of thrombus layering, as identified by duplex scanning, a residual stenosis, or the presence of intraluminal post-thrombotic scar tissue.

From February 2018 to January 2023, 141 women with a pelvic venous disorder secondary to IVS and OVR were identified. Table I outlines the demographics of this patient cohort. The average age was 44.7 ± 10.5 years with 3.18 ± 1.82 pregnancies. The racial distribution was as follows: Caucasian 60%, African American 10%, Hispanic 8%, Asian 1%, mixed 1%, and 20% either declined to identify or were not recorded. The average follow-up time for the entire cohort was 12 ± 12.1 months. Figs 1 and 2 demonstrate the vein territories covered and the stent types, diameters, and lengths, respectively. The most common vein territories covered were from the IVC to the left external iliac vein in 83% and the IVC to the right external iliac veins in 13%. Types of stents deployed were Venovo (Becton Dickinson, Tempe, AZ) 48 (34%), Wallstent (Boston Scientific, Marlborough, MA) 14 (10%), and Abre (Medtronic, Minneapolis, MN) 79 (56%). The most common diameter and stent lengths used were 14 and 16 mm and 149 and 150 mm, respectively. Pelvic and dyspareunia VAS scores preintervention, 3, 6, 12, 24, and 36 months after the intervention were as follows: 6.4 ± 73 (n = 141), 2.6 ± 3.3(n = 98), 1.71 ± 2.83 (n = 77), 2.04 ± 3.5 (n = 76), 2.4 ± 3.7 (n = 30), and 1.15 ± 3 (n = 13) ( P ≤ .001) ( Fig 3 ). Of the entire cohort, no patient required bilateral ovarian vein and pelvic reservoir embolization. Pelvic reservoirs were present in 113 of 141 patients (83%). Table I Demographics of patients with combined iliac vein stenoses and ovarian vein reflux treated with iliac vein stenting alone Characteristics Female 141 Average age, years 44.72 ± 10.50 Average gravida 3.18 ± 1.82 Average BMI 29.59 ± 7.76  Race  White 85 (60.3)  Unknown 18 (12.8)  African American 15 (10.6)  Hispanic 11 (7.8)  Declined to specify 9 (6.4)  Multiracial 2 (1.4)  Asian 1 (0.7) Medical history  Diabetes mellitus 10 (7.1)  Hypertension 39 (27.7)  Coronary artery disease 2 (1.4)  Hyperlipidemia 25 (17.7)  Endometriosis 7 (4.9)  Uterine fibroids 2 (1.4)  Ovarian cysts 2 (1.4)  Cancer 11 (7.8)  Thyroid disease 13 (9.2)  Arthritis 35 (24.8)  Sciatica 2 (1.4) Values are mean ± standard deviation or number (%). Fig 1 Iliac vein territories covered by stents. IVC , inferior vena cava; LC I V , left common iliac vein; LEIV , left external iliac vein; RCIV , right common iliac vein; RCFV , right common femoral vein; REIV , right external iliac vein. Fig 2 Stent types, diameters, and lengths used to treat women with iliac vein stenoses and a pelvic venous disorder. Fig 3 Visual analog scale ( VAS ) pain scores in women with iliac vein stenoses, treated with iliac vein stenting before intervention, 3, 6, 12, 24, and 36 months after intervention. All VAS scores are significantly improved compared to preintervention scores. Scores improve up to 6 months. No significant differences are noted after 6 months. Demographics of patients with combined iliac vein stenoses and ovarian vein reflux treated with iliac vein stenting alone Values are mean ± standard deviation or number (%). Iliac vein territories covered by stents. IVC , inferior vena cava; LC I V , left common iliac vein; LEIV , left external iliac vein; RCIV , right common iliac vein; RCFV , right common femoral vein; REIV , right external iliac vein. Stent types, diameters, and lengths used to treat women with iliac vein stenoses and a pelvic venous disorder. Visual analog scale ( VAS ) pain scores in women with iliac vein stenoses, treated with iliac vein stenting before intervention, 3, 6, 12, 24, and 36 months after intervention. All VAS scores are significantly improved compared to preintervention scores. Scores improve up to 6 months. No significant differences are noted after 6 months. The average follow-up time for the entire cohort was 12.0 ± 12.1 months (median, 10.65 months). Stent reinterventions were required in 19 of the 141 patients (13%) ( Table II ). The average time to the first reintervention was 14.0 ± 10.6 months. All reinterventions were for symptom recurrences and 17 of 19 reinterventions were in patients who received Nitonol stents as their initial intervention. Of the 19 reinterventions, 11 were for new contralateral iliac vein lesions that required additional stenting. Three reinterventions were on the index stent and all three required distal stent extensions for either missed or new inflow stenoses. Five patients had contralateral stents and ipsilateral reinterventions. Three ipsilateral reinterventions were secondary to in-stent restenosis and were treated with relining the original stent. Four of the ipsilateral reinterventions in this group required distal stent extensions into the common femoral vein. Overall, seven of the eight ipsilateral reinterventions required distal stent extension into the common femoral vein. In-stent restenosis was the indication for reintervention in only 2% of the entire cohort. Table II Table outlining indications for re-intervention and vein territories treated No. of patients Average No. of stents Average time to first reintervention Indication Reintervention type Ipsilateral 3 2.30 ± 0.50 8.00 ± 9.60 Symptom recurrence: 3 Distal extension: 3 Contralateral 11 2 18.8 ± 14.4 Symptom recurrence: 11 Contralateral stenting: 11 Both 5 3 11.8 ± 10.1 Symptom recurrence: 2 Symptom recurrence from in-stent restenosis: 2 Relining: 3 Distal stent extension into common femoral vein: 2 Table outlining indications for re-intervention and vein territories treated

It is currently well-accepted that, among venous specialists, PVI is a common cause of chronic pelvic pain in women. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 19 , 25 , 26 , 27 The abdominal and pelvic venous hemodynamics associated with reflux and obstruction and pain generation are complex and incompletely understood. PVI can occur secondary to reflux with or without outflow obstruction. Despite the numerous flow patterns that can occur with PVI, patient can be separated into several broad categories: (1) isolated OVR, (2) isolated iliac vein outflow obstruction, (3) combined OVR and obstruction, and (4) left renal vein obstruction. All of these flow patterns can occur with or without a pelvic reservoir, which is postulated to contribute to the development of pelvic pain. There are numerous controversies as to the optimal management of these flow patterns and which strategy is associated with low complication/reintervention rates and sustained long-term pain reduction. The major controversy currently facing clinicians is the appropriate treatment strategy to use in the management of patients with symptomatic PVI. For example, in women with isolated OVR, embolization is the current standard. However, there is no consensus as to how many vessels should be embolized or the type of embolization technique to use. Table III lists the results of various embolization treatment strategies and their results. Treatments range from unilateral left OVE to bilateral ovarian and internal iliac vein embolization with coils, plugs, and/or sclerosants. The report by De Gregorio et al 34 is the only large scale clinical review of four-vessel embolization performed using coils and plugs alone with excellent 5-year follow-up. This investigation specifically excluded patients with iliac vein outflow disease. In this investigation, technical success was reported as follows: Four-vessel embolization (bilateral ovarian and internal iliac veins) in 85.0%, three vessels (bilateral internal iliac and left ovarian vein) in 11.5%, two vessels (left internal and ovarian veins) in 3.46%, and one vessel (left ovarian vein) in 0.19%. The average preintervention VAS score of 7.63 ± 0.90 was reduced to 0.91 ± 1.50 after the intervention and sustained for ≤5 years. Recurrence of symptoms was observed in 5.0% of patients, 1.9% demonstrated coil migration, and 15.1% reported postembolization abdominal pain that was treated solely with nonsteroidal anti-inflammatory medications. These data clearly suggest that aggressive embolization of all sources of reflux is associated with excellent and sustained long-term pain reduction. However, the results reported in Table III suggest that similar results can be obtained with limited, less aggressive embolization. To date, there are no studies comparing four-vessel embolization with ovarian vessel embolization alone. Similarly, there are no data on the necessity to embolize a pelvic reservoir. Table III Table outlining results of ovarian vein embolization and methods used to assess treatment outcomes Study Year published No. of patients Veins treated Embolization technique Mean follow-up, months Clinical outcome VAS scores Maleux et al 28 2000 41 32 LOV, 9 B/l OV Glue 19.9 58.5% significant improvement, 9.7% partial, 4% none None Venbrux et al 20 2002 56 56 B/L OV, 43 B/L IIV Sclerosant + coils 22.1 96% significant/partial, 4% none 7.80 to 2.70 at 12 months Pieri et al 29 2003 33 1 ROV, 11 LOV, 21 B/L OV Sclerosant 12 100% significant None Kim et al 17 2006 127 106 B/L OV, 95 B/L IIV, 23 Unilateral IIV Sclerosant + coils 45 85% significant, 12% none, 3% worse 7.60 ± 1.80 to 2.90 ± 2.80 Kwon et al 30 2007 67 64 LOV, 1 ROV, 2 B/L OV Coils 44.8 82% significant, 15% none, 3% worse None Creton et al 16 2007 24 24 LOV, 10 ROV Coils 36 68% significant 5.30 to 3.10 at one month Gandini et al 31 2008 38 38 B/L OV STS foam 12 100% significant 7.80 ± 1.80 to 2.70 ± 2.80 Asciutto et al 15 2009 35 35 LOV and IIV Coils 45 Significant improvement 5.20 ± 3.50 to 1.20 ± 0.90 Laborda et al 32 2013 179 202 LOV, 193 ROV, 184 L IIV, 149 R IIV Coils 60 Significant improvement 7.34 ± 0.70 to 0.78 ± 2.80 Santoshi et al 1 2018 38 38 LOV Sclerosants + coils 3 35% complete resolution, 54% partial, 5% none 7.41 ± 1.33 to 3.15 ± 3.10 Guirola et al 33 2018 100 B/L OV, IIV Coils and plugs 12 Relief in 90% N/A De Gregorio et al 34 2019 520 84.5% (LOV, ROV, RIIV, LIIV) 11.5% (LOV, RIIV, LIIV) 3.5% (LOV, LIIV) 0.2% (LOV) Coils or plugs 59 Significant resolution 7.63 ± 0.90 to 0.90 ± 1.50 B/L, Bilateral; IIV, internal iliac vein; LIIV, left internal iliac vein; L, left; LOV, left ovarian vein; RIIV, right internal iliac vein; ROV, right ovarian vein. Table outlining results of ovarian vein embolization and methods used to assess treatment outcomes B/L, Bilateral; IIV, internal iliac vein; LIIV, left internal iliac vein; L, left; LOV, left ovarian vein; RIIV, right internal iliac vein; ROV, right ovarian vein. In patients with symptomatic PVI secondary to isolated iliac vein stenoses, iliac vein stenting is the current standard of care. The major concern with iliac vein stenting is long-term patency. The average age of women receiving iliac vein stents in the current investigation is 44.7 ± 10.5 years and mirrors our previous publications. 1 , 10 , 22 There are currently no reports on long-term adverse outcomes associated with either early or late venous stent thrombosis. The concern is that a stent occlusion may cause venous thrombo-=embolic events, the development of post-thrombotic syndrome, or limb-threatening outflow obstruction. This clinical uncertainty demands caution when placing venous stents in all patients but is especially concerning in younger patients in their twenties and thirties. A report by Sulakvelidze et al 10 indicated that venous stenting in women in their 20s was associated with poor outcomes and emphasized the need to perform a thorough evaluation for alternative pelvic pain etiologies in this patient cohort. To our knowledge, this investigation is the first to assess long-term treatment outcomes in women with combined OVR and iliac vein outflow disease, treated with iliac vein stenting alone. Our current investigation confirmed the results observed in our previous investigation of 38 women, which reported complete resolution of pelvic symptoms in 78% of women up to 6 months. 22 We observed similar results in the 141 women evaluated with sustained results up to 3 years. As in our previous report, none of the women in the current cohort required reintervention with OVE for persistent or recurrent symptoms despite the presence of a pelvic reservoir in 83% of patients. The majority of reinterventions were performed for symptom recurrences secondary to the development of contralateral iliac vein lesions or untreated lesions distal to the index stent requiring a stent extension. Only three patients required reintervention to the index stent due to the development of in-stent stenosis. The major issue the current investigation raises is the role that OVR plays in women with concomitant iliac vein outflow stenoses. The underlying premise for pain generation is venous hypertension. It is clear that in isolated OVR or isolated iliac vein outflow obstruction, these individual anatomic lesions are the source of venous hypertension. It is not clear, in patients with concomitant venous abnormalities which lesion is predominantly responsible for symptom generation. The only investigation to try and determine the role of reflux and obstruction in pain resolution is from Santoshi et al. 1 This investigation treated a group of women with concomitant disease with embolization followed by stenting. Pain reduction was only observed after venous stenting was performed. The criticism of this investigation was that the time interval between embolization and stenting was only 2 to 4 weeks. Expert opinion from thought leaders suggests that it may take ≤6 months after embolization before patients experience significant symptom resolution. The current investigation however, supports the observations reported by Santoshi et al. 1 Significant symptom resolution was observed at one month and continued up to three months. After 3 months, no further improvement was observed. No patient who developed symptom recurrence after stenting required embolization and the presence of a pelvic reservoir did not seem to predict treatment failure. To determine the role of OVR in patients with concomitant disease, embolization must be performed first and the need for iliac vein stenting should not be considered for ≥6 months after embolization. This evaluation is necessary, especially in young women. The life-long consequences of iliac vein stent failure in this treatment group is a legitimate concern and should be factored into the decision-making process when assessing patients with disabling, chronic pelvic pain secondary to PVI that affects patient quality of life.

PVI is a known cause of chronic pelvic pain. In patients with isolated OVR or isolated iliac vein outflow obstruction, embolization and stenting, respectively, are currently the standard of care. In patients with concomitant OVR and iliac vein outflow obstruction, our data indicate that patients are best treated with iliac vein stenting alone. Continued pelvic pain reduction is observed for ≤3 months after intervention and sustained in the long term. Symptom recurrence is secondary to the development of new contralateral iliac vein lesions or the need for stent extension for residual disease. Symptom recurrence typically occurs within the first 24 months after the intervention and emphasizes the need for long-term clinical follow-up. OVE for symptom recurrence was not required in this patient cohort and a pelvic reservoir was not predictive of treatment failure with stenting alone.

The major limitation of this investigation is that it is a retrospective analysis of prospectively collected data. Furthermore, OVR was assessed only by venography of the left renal vein and left ovarian veins. Right ovarian vein cannulations and/or balloon occlusion venography of the internal iliac veins were not performed. All iliac lesions treated were nonthrombotic lesions therefore the generalizability of these findings to patients with post-thrombotic iliac vein stenoses is unknown. For example, the reintervention rate in women with post-thrombotic disease will most likely be higher and the long-term stent patency lower.

None.