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Development of a condition‐specific patient‐reported outcome measure for measuring symptoms and appearance in vascular malformations: the OVAMA questionnaire

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Summary Background The symptoms and appearance of vascular malformations can severely harm a patient’s quality of life. The aim of treatment of vascular malformations generally is to improve condition‐specific symptoms and/or appearance. Therefore, it is highly important to start testing treatment effects in clinical studies from the patient’s perspective. Objectives The objective of this study was to develop a patient‐reported outcome measure (PROM) for measuring symptoms and appearance in patients with vascular malformations. Methods A first draft of the PROM was based on the previously internationally developed core outcome set. The qualitative part of this study involved interviews with 14 patients, which led to a second draft. The second draft was field‐tested cross‐sectionally, after which groups of items were evaluated for adequate internal consistency (Cronbach’s alpha >0.7) to form composite scores. Construct validity was evaluated by testing 13 predefined hypotheses on known‐group differences. Results The patient interviews ensured adequate content validity and resulted in a general symptom scale with 6 items, head/neck symptom scale with 8 items and an appearance scale with 9 items. Cronbach’s alpha was adequate for two composite scores: a general symptom score (0.88) and an appearance score (0.85). Ten out of 13 hypotheses on known‐group differences were confirmed, confirming adequate construct validity. Conclusions With the development of the OVAMA questionnaire, outcomes of patients with vascular malformations can now be evaluated from the patients’ perspective. This may help improve the development of evidence‐based treatments and the overall care for patients with vascular malformations.
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... Therefore, the aim of this study is to examine appearance-related concerns in patients with VMs by using the condition-specific OVAMA (Outcome measures for VAscular MAlformations) questionnaire. 4,13,14 Furthermore, we assessed how the appearance of VMs affects HR-QoL in these patients. ...
... The OVAMA-questionnaire is a condition-specific PROM for patients with VMs, which focuses on VM symptoms and appearance (supplement 1). 4,13,14 The OVAMA-questionnaire addresses appearance of the VM with the following items: patient-reported size, swelling, colour difference, texture difference, facial distortion, bodily distortion, being stared at, reduced self-esteem due to the appearance of the VM, and dissatisfaction with appearance. All questions refer to issues occurring in the last four weeks. ...
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Background Peripheral vascular malformations (VMs) may lead to disfigurement of the body and face, potentially impairing aesthetic appearance. Yet, data on appearance in this population is limited. This study aimed to examine appearance-related concerns and their impact on health-related quality of life (HR-QoL) in patients with VMs. Methods In this cross-sectional study, 384 adults and 194 children with VMs were invited to complete the Outcome Measures for VAscular MAlformations (OVAMA) questionnaire to evaluate potential appearance-related concerns on a five-point verbal-rating scale, higher scores indicate more appearance-related concerns (e.g. colour-difference, facial-distortion, reduced self-esteem, and dissatisfaction with appearance). HR-QoL was evaluated using Patient-Reported Outcome Measurement Information System (PROMIS). Subgroups of patients reporting more appearance-related concerns were identified using univariate analysis. Associations between appearance-related concerns and various HR-QoL domains (e.g. anxiety and social-participation) were assessed. Results 184 patients (32%) completed the questionnaires;121 patients (66%) reported that one or more appearance-outcome was severely affected (i.e.4-5 out of 5). The following factors statistically significant associated with more appearance-related concerns: capillary/combined origin, facial localization, subcutaneous tissue involvement, larger size, overgrowth, and diagnosis of a syndrome. In adults, dissatisfaction with appearance and reduced self-esteem due to the VM correlated with more anxiety and depression symptoms. Reduced self-esteem correlated with less social-participation. In children, bodily-distortion and being stared at were correlated with less peer relationships. Conclusion Severe appearance-related concerns were present in two-thirds of patients with VMs, impairing their mental HR-QoL. Clinicians should acknowledge appearance-related aspects, monitor psychological well-being, and offer intervention aimed at improving satisfaction with appearance.
... Thus, it is timely that in this issue of the BJD, development of a patient-reported outcome measure addressing symptoms and appearance in vascular malformations (OVAMA questionnaire) is presented. 1 Advances in cell biology and genomics have led to recognition of the role of gene mutations in the development of vascular malformations in at least two intracellular signalling pathways: RAS/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3 kinase (PIK3)/protein kinase B/mammalian target of rapamycin (mTOR). 2 These discoveries, providing insight into pathogenesis, have consequently led to the development of targeted interventions. 3 The median cost for research and development of therapeutic agents to introduce a new drug to market, inclusive of costs for failed trials, has been estimated at US$980 million (in 2018 dollars). Within the class of antineoplastic and immunomodulatory interventions, the estimated cost was three times higher at US$2771 million. ...
... 7 In the absence of a measure addressing the core domains of symptom severity and appearance, the authors undertook development of such a patient-reported outcome measure for interventional clinical trials in peripheral vascular malformations. 1 As we enter a new era of formal clinical trials of innovative treatments uncovered by careful iterative research, let us hope that the same care and attention will also be applied by trialists to selecting the outcome measures that matter most: to patients, clinicians and other relevant stakeholderscore outcome sets. ...
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Linked Article: Lokhorst et al. Br J Dermatol 2021; 185:797–803.
... The systematic review for vascular malformations also showed low-quality rating systems 17 . Therefore, a new PROM questionnaire is now in development; the Outcome Measures for Vascular Malformations (OVAMA) questionnaire 27 . For burn scars, both PROMs, clinician reported rating systems and objective measurement instruments are available 28 . ...
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Background Congenital melanocytic naevi (CMN) can impact on patients’ lives due to their appearance and the risk they carry of neurological complications or melanoma development. Development of a core outcome set (COS) will allow standardised reporting and enable comparison of outcomes. This will help to improve guidelines. In previous research, relevant stakeholders reached a consensus over which core outcomes should be measured in any future care or research. The next step of the COS development is to select the appropriate measurement instruments. Aim Step 1: to update a systematic review identifying all core outcomes and measurement instruments available for CMN. Step 2: to evaluate the measurement properties of the instruments for the core outcomes. Methods This study was registered in PROSPERO and performed according to the PRISMA checklist. Step 1 includes a literature search in EMBASE (Ovid), PubMed and the Cochrane Library to identify core outcomes and instruments previously used in research of CMN. Step 2 yields a systematic search for studies on the measurement properties of instruments that were either developed or validated for CMN, including a methodological quality assessment following the COSMIN methodology. Results Step 1 included twenty-nine studies. Step 2 yielded two studies, investigating two quality of life measurement instruments. Conclusion Step 1 provided an overview of outcomes and instruments used for CMN. Step 2 showed that additional research on measurement properties is needed to evaluate which instruments can be used for the COS of CMN. This study informs the instrument selection and/or development of new instruments.
... There is still an absence of observational natural history studies and clinically meaningful outcome measures for therapeutic interventions for vascular anomalies. Significant strides are being made to develop outcome measures that capture patient values and address the heterogeneity of this patient population ( Lokhorst et al., 2021 ). Because gene discovery is outpacing the understanding of the resultant downstream molecular effects and genotypephenotype correlations, patients are receiving off-label drugs outside of clinical trials in hopes of relieving symptoms; however, validated outcome measures of therapeutic response are lacking. ...
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Vascular anomalies comprise an array of congenital developmental disorders that can lead to significant disfigurement and physiologic disarray. The vast multitude of clinical phenotypes has inherently led to misdiagnosis and patients and families enduring long diagnostic odysseys of medical care. Although the observed variation in disease manifestations remains poorly understood, targeted next-generation sequencing has pivoted our understanding of the pathobiology of vascular anomalies and, for the first time, uncovered potential pharmacologic targets for these disorders. In this review article, we highlight current and developing targeted therapies for vascular anomalies, namely phosphoinositide 3-kinase and mitogen-activated protein kinase pathway inhibitors, and discuss the future directions of targeted therapies.
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Purpose The aim of this observational study was to assess Health-Related Quality of Life (HRQOL) changes in patients with vascular malformations, over a period of almost eight years, and to assess clinical and demographic characteristics possibly associated with HRQOL changes. Methods 80 out of 111 patients who were included in a previously published comparative HRQOL study accepted inclusion in this follow-up study. HRQOL at baseline and follow-up was assessed with the Short-Form 36-item questionnaire (SF-36). Median observation time was 7.9 years. Linear mixed models and linear regression models were applied to assess HRQOL change and possible associations with demographic- and clinical variables. Results The median age of the patient cohort at baseline evaluation (n=111) was 27.0 years. 96 out of 111 (86.5%) patients were diagnosed with venous malformations. Significantly higher SF-36 scores at follow-up were found for the physical domains Role limitations due to (RLDT) physical problems (difference=13.5; 95% CI [1.6, 25.3]) and Bodily pain (difference=11.3; 95% CI [3.8, 18.8]). No deterioration of HRQOL was found in any domain. In multivariate analyses, female gender, muscle/bone involvement and higher age were associated with a positive relative change in SF-36 in the domains Physical functioning, RLDT physical problems and RLDT emotional problems, respectively. Invasive treatment was not associated with long-term HRQOL-change. Conclusions Over a period of almost eight years, significant improvement of SF-36 scores was observed in the physical domains RLDT physical problems and Bodily pain. Female gender, muscle/bone involvement and higher age were associated with HRQOL improvement in certain domains.
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Arteriovenous malformations (AVMs) are fast-flow lesions that may be destructive and are the most difficult-to-treat vascular anomalies. Embolization followed by surgical resection is commonly used; however, complete resection is rarely possible and partial resection often leads to dramatic worsening. Accumulating data implicate abnormal angiogenic activity in the development of AVMs. Thalidomide has been reported as an inhibitor of vascular proliferation. Here, we report a prospective experimental observational study testing the effects of the angiogenesis inhibitor thalidomide on 18 patients with a severely symptomatic AVM that is refractory to conventional therapies. All patients experienced a rapid reduction in pain, cessation of bleeding, and ulcer healing. Cardiac failure resolved in all three affected patients. Reduced vascularity on arteriography was observed in two patients. One AVM appeared to be cured after 19 months of thalidomide and an 8-year follow-up. Eight AVMs were stable after a mean thalidomide cessation of 58 months, and four lesions recurred after 11.5 months. Combined treatment with embolization permitted dose reduction in five patients with clinical improvement. Grade 3 side effects were dose dependent, including asthenia (n = 2) and erythroderma (n = 2). The results suggest that thalidomide is efficacious in the management of chronic pain, bleeding and ulceration of extensive AVMs that are refractory to conventional therapy. Further clinical study is needed to confirm the safety and efficacy of thalidomide treatment in AVM. Boon et al. show that thalidomide appears to be efficacious in the management of chronic pain, bleeding and ulceration in 18 patients with severely symptomatic arteriovenous malformations refractory to conventional therapies.
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Auricular arteriovenous malformations (AVMs) can cause a variety of symptoms that seriously impact the patient's appearance, life, and mental well‐being. Surgery is the primary management method for auricular AVMs, but there is no consensus on how to surgically manage auricular AVMs. In this article, we document a comprehensive review of the characteristics, classification, and surgical interventions to treat auricular AVMs. Auricular arteriovenous malformations (AVMs) can cause a variety of symptoms that seriously impact the patient's appearance, life, and mental well‐being. Surgery is the primary management method for auricular AVMs, but there is no consensus on how to surgically manage auricular AVMs. In this article, we document a comprehensive review of the characteristics, classification, and surgical interventions to treat auricular AVMs.
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Objective Vascular malformations can negatively impact the patient’s quality of life. Pain is a common problem in these patients. The aim of this study was to investigate risk factors associated with pain and to assess how pain affects quality of life. Methods This prospective cross-sectional study was conducted in a tertiary vascular anomaly expertise center. Between June and December 2020, all patients from our local database (334 adults and 189 children) with peripheral vascular malformations were invited to complete the Outcome Measures for VAscular MAlformations (OVAMA) questionnaire to evaluate the presence, frequency, and intensity of pain. Additionally, patients were asked to complete several Patient-Reported Outcome Measurement Information System (PROMIS) scales to evaluate their quality of life. Risk factors associated with pain were identified in bivariate analysis and multivariable logistic regression. Quality of life domains were compared between patients who experienced pain and patients who did not. Results A total of 164 patients completed the questionnaire about pain and 133 patients completed all quality of life questionnaires. Approximately half of the patients (52%) reported pain in the past four weeks and 57% of these patients reported pain daily or several times a week. Female gender (p=0.009), lesions located in the upper extremity (p<0.001) or lower extremity (p<0.001), and intramuscular/intraosseous lesions (p=0.004) were independently associated with the presence of pain. The following quality of life domains were diminished in patients who experienced pain in comparison to patients who did not: pain interference (p<0.001), physical functioning (p<0.001), and social participation (p<0.001) in adults, and pain interference (p=0.001), mobility (p=0.001), and anxiety (p=0.024) in children. Conclusion Pain is a frequently reported complaint in patients with vascular malformations and is present in approximately half of the patients. Patients with lesions located in the upper or lower extremity, intramuscular/intraosseous lesions, and female patients are more likely to experience pain. The presence of pain negatively impacted patients’ quality of life. Although VM are a benign condition and expectative management is frequently applied, our study shows that pain is a serious concern and needs to be actively assessed. Pain is a sign of various etiologies, which should be examined in order to properly treat the pain.
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Introduction: The OVAMA (Outcome measures for vascular malformations) project determined quality of life (QoL) as a core outcome domain for patients with vascular malformations. In order to measure how current therapeutic strategies alter QoL in these patients, a patient-reported outcome measurement (PROM) responsive to changes in QoL is required. We therefore assessed the responsiveness of two widely used generic QoL PROMs, the Medical Outcomes Study Short Form 36 (SF-36) and Skindex-29, in adult patients with vascular malformations. Methods: In an international multicentre prospective study, treated and untreated patients completed the SF-36 and Skindex-29 at baseline and after a follow-up period of 6-8 weeks. Global Rating of Change (GRC) scales assessing various QoL-related outcome domains were additionally completed. Per subscale, responsiveness was assessed using two methods: by testing hypotheses on expected correlation strength between change scores of the questionnaires and the GRC scales, and by calculating the area under the receiver operating characteristics curve (AUC). The questionnaires were considered responsive if ≥75% of the hypotheses were confirmed or if the AUC was ≥0.7. Results: Eighty-nine participants were recruited in three centres in the Netherlands and United States, of which 67 completed all baseline and follow-up questionnaires. For all subscales of the SF-36 and Skindex-29, less than 75% of the hypotheses were confirmed and the AUC was <0.7. Discussion: Our findings suggest that the SF-36 and Skindex-29 seemed unresponsive to change in QoL. This suggests that alternative PROMs are needed to measure - and ultimately improve - QoL in patients with vascular malformations.
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Purpose The Outcome measures for vascular malformation (OVAMA) group reached consensus on the core outcome domains for the core outcome set (COS) for peripheral vascular malformations (venous, lymphatic and arteriovenous malformations). However, it is unclear which instruments should be used to measure these domains. Therefore, our aims were to identify all outcome measurement instruments available for vascular malformations, and to evaluate their measurement properties. Methods With the first literature search, we identified outcomes and instruments previously used in prospective studies on vascular malformations. A second search yielded studies on measurement properties of patient- and physician-reported instruments that were either developed for vascular malformations, or used in prospective studies. If the latter instruments were not specifically validated for vascular malformations, we performed a third search for studies on measurement properties in clinically similar diseases (vascular or lymphatic diseases and benign tumors). We assessed the methodological quality of these studies following the Consensus-based Standards for the selection of health Measurement Instruments methodology, and evaluated the quality of the measurement properties. Results The first search yielded 27 studies, none using disease-specific instruments. The second and third search included 22 development and/or validation studies, concerning six instruments. Only the Lymphatic Malformation Function Instrument was developed specifically for vascular malformations. Other instruments were generic QoL instruments developed and/or partly validated for clinically similar diseases. Conclusions Additional research on measurement properties is needed to assess which instruments may be included in the COS. This review informs the instrument selection and/or the development of new instruments. Systematic review registration PROSPERO, 42017056242.
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There is a variety of outcome reporting in the clinical research on peripheral vascular malformations including capillary, venous, lymphatic, arteriovenous and combined malformations. Without harmonization of outcome measures, treatments cannot be properly compared. This hampers the development of evidence‐based treatment guidelines, urgently needed for these challenging congenital conditions. The mission of the Outcome measures for VAscular MAlformations (OVAMA) project is to uniform outcome reporting in clinical research. This article is protected by copyright. All rights reserved.
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Importance Patients with vascular malformations (VAMs) and vascular overgrowth syndromes have lower health-related quality of life (HRQoL) attributable to social stigmatization, poor mental health, severity, and pain. However, the factors that contribute to this decreased HRQoL are not clear. Objective To perform a systematic review and meta-analysis of studies that used validated HRQoL instruments to compare the HRQoL of persons with VAMs with the US general population. Data Sources A comprehensive search was performed in MEDLINE, Embase, PsycINFO, CINAHL, and Scopus from 1946 to March 31, 2017, with the consultation of an experienced librarian. Study Selection All VAM studies with validated HRQoL instruments published in the English language were included. Case reports, review articles, non–English-language publications, and studies about the development of new HRQoL instruments were not included. Data Extraction and Synthesis Two reviewers assessed studies’ eligibility and the risk of bias and performed data extraction. The meta-analysis was performed using the random-effects model. Comparisons of means were performed using the unpaired, 2-sample t test. Main Outcomes and Measures The outcome was HRQoL. Results Eleven studies met the inclusion criteria for a total of 692 patients with VAMs. Six studies (320 patients) were included in the meta-analysis, whereas 5 studies were included in the qualitative analysis (372 patients). Those with VAMs had lower 36-Item Short-Form Health Survey scores in bodily pain (mean difference, −11.87; 95% CI, −21.45 to −2.29; I² = 92%; P = .02) and mental health (mean difference, −6.04; 95% CI, −11.55 to −0.52; I² = 83%; P = .03) compared with the US general population. Conclusions and Relevance Patients with VAMs had increased pain and psychosocial distress compared with the US general population. Pain and psychological morbidity are associated with poorer HRQoL and may serve as indicators for quality of life.
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Background: An important limitation in vascular malformation research is the heterogeneity in outcome measures used for the evaluation of treatment outcome. Objective: The Outcome measures for VAscular MAlformations (OVAMA) project aimed to reach international consensus on a core outcome set (COS) for clinical research on peripheral vascular malformations: lymphatic (LM), venous (VM) and arteriovenous malformations (AVM). In this consensus study, we determined what domains should constitute the COS. Methods: Thirty-six possibly relevant outcome domains were proposed to an international group of physicians, patients and the parents of patients. In a 3-round e-Delphi process using online surveys, participants repeatedly rated the importance of these domains on a 5-point Likert scale. Participants could also propose other relevant domains. This process was performed for LM, VM and AVM separately. Consensus was pre-defined as 80% agreement on the importance of a domain amongst both the physician group and the patient/parent group. Outcomes were then reevaluated in an online consensus meeting. Results: 167 physicians and 134 patients and parents of patients with LM (n=50), VM (n=71) and AVM (n=29) participated in the study. After three rounds and a consensus meeting, consensus was reached for all three types of vascular malformations on the core domains of radiological assessment, physician-reported location-specific signs, patient-reported severity of symptoms, pain, quality of life, satisfaction and adverse events. Vascular malformation type-specific signs and symptoms were included for LM, VM and AVM, separately. Conclusion: It is recommended to measure at least these core outcome domains in therapeutic-efficacy studies on peripheral vascular malformations. This article is protected by copyright. All rights reserved.
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Introduction Low-flow vascular malformations are congenital abnormalities of the veins, capillaries or lymphatic vessels or a combination of the previous. Compressive garments are frequently used as a first-line treatment option for low-flow vascular malformations of the extremities with the purpose of relieving symptoms. Yet, the benefits and harms of compression stockings remain unclear. Methods A systematic search was performed in MEDLINE, Embase, Cochrane Central Register of Controlled Trials including a hand search for studies measuring the benefits and harms of compression garments in treating low-flow vascular malformations. Two investigators performed study selection, quality assessment and data extraction independently. Results Of the 565 studies found, eventually five (totalling 101 patients with venous malformations or Klippel–Trenaunay syndrome receiving compression therapy) observational studies were included in the systematic review. Although the overall quality of these studies was poor, results suggest that compression garments might lessen intravascular coagulation, improve symptoms and appearance, diminish oedema, and protect against minor trauma. None of the studies quantified any harms of compression therapy. Conclusion Even though compression therapy is commonly used in the treatment of low-flow vascular malformations, available literature does not provide high-quality evidence to validate its use. We therefore advocate the need for prospective comparative trials with standardised outcome measures to study the benefits and harms of this treatment option.
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Background Rare diseases (RDs) affect a small number of people within a population. About 5000 to 8000 distinct RDs have been identified, with an estimated 6% to 8% of people worldwide suffering from an RD. Approximately 75% of RDs affect children. Frequently, these conditions are heterogeneous; many are progressive. Regulatory incentives have increased orphan drug designations and approvals. Objective To develop emerging good practices for RD outcomes research addressing the challenges inherent in identifying, selecting, developing, adapting, and implementing patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments for use in RD clinical trials. Good Practices for Outcomes Research This report outlines the challenges and potential solutions in determining clinical outcomes for RD trials. It follows the US Food and Drug Administration Roadmap to Patient-Focused Outcome Measurement in Clinical Trials. The Roadmap consists of three columns: 1) Understanding the Disease or Condition, 2) Conceptualizing Treatment Benefit, and 3) Selecting/Developing the Outcome Measure. Challenges in column 1 include factors such as incomplete natural history data and heterogeneity of disease presentation and patient experience. Solutions include using several information sources, for example, clinical experts and patient advocacy groups, to construct the condition’s natural history and understand treatment patterns. Challenges in column 2 include understanding and measuring treatment benefit from the patient’s perspective, especially given challenges in defining the context of use such as variations in age or disease severity/progression. Solutions include focusing on common symptoms across patient subgroups, identifying short-term outcomes, and using multiple types of COA instruments to measure the same constructs. Challenges in column 3 center around the small patient population and heterogeneity of the condition or study sample. Few disease-specific instruments for RDs exist. Strategies include adapting existing instruments developed for a similar condition or that contain symptoms of importance to the RD patient population, or using a generic instrument validated for the context of use. Conclusions This report provides state-of-the-art solutions to patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments challenges in clinical trials of patients with RDs. These recommended solutions are both pragmatic and creative and posed with clear recognition of the global regulatory context used in RD clinical development programs.
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Objective: To evaluate complications of pregnancy, including thromboembolism, in women with extensive vascular malformations associated with Klippel-Trenaunay Syndrome (KTS). Design: Nationwide cross-sectional study. Setting: Two tertiary expert centers and the Dutch Klippel-Trenaunay patient organization. Sample: Adult women with KTS. Methods: Patients with KTS were invited to participate in a comprehensive online survey about their obstetric history. Reference data on pregnancy outcomes and complications of non-diseased women were collected from population-based cohorts from the literature. Main outcome measures: Prevalence of complications, specifically venous thromboembolism and postpartum hemorrhage. Results: Sixty women completed the survey. Seventeen patients did not conceive, of which three refrained from pregnancy because of KTS. A total of 97 pregnancies and 86 deliveries were reported in 43 patients. KTS-related symptoms aggravated during pregnancy in 43% of patients. Deep vein thrombosis was present in 5.8% and pulmonary embolism in 2.3% of pregnancies, which was extremely high compared to the reference population (p<0.0001) with a relative risk of 108.9 (95% CI 46.48-255.03) and 106.2 (95% CI 26.97-418.10) respectively. Severe postpartum hemorrhage (PPH) occurred in 11% of KTS pregnancies, compared to 5.8% of pregnancies of the reference population (RR 1.81, 95% CI 0.97-3.37, p=0.06). Conclusions: Our data suggest that women with KTS have a significant risk of venous thromboembolic events, severe postpartum hemorrhage and aggravation of KTS symptoms during pregnancy and early postpartum period. Obstetricians should counsel patients about these risks in the preconception phase. Antithrombotic prophylaxis should be considered in the obstetric management of KTS patients.