CLINICAL GUIDELINE

Annals of Internal Medicine

Second International Guidelines for the Diagnosis and Management of
Hereditary Hemorrhagic Telangiectasia
Marie E. Faughnan, MD, MSc; Johannes J. Mager, MD, PhD; Steven W. Hetts, MD; Valerie A. Palda, MD, MSc; Kelly Lang-Robertson;
Elisabetta Buscarini, MD; Erik Deslandres, MD; Raj S. Kasthuri, MD; Andrea Lausman, MD; David Poetker, MD, MA; Felix Ratjen, MD;
Mark S. Chesnutt, MD; Marianne Clancy, RDH, MPA; Kevin J. Whitehead, MD; Hanny Al-Samkari, MD; Murali Chakinala, MD;
Miles Conrad, MD; Daniel Cortes, BscPhm; Claudia Crocione; Jama Darling, MD; Els de Gussem, MD; Carol Derksen;
Sophie Dupuis-Girod, MD, PhD; Patrick Foy, MD; Urban Geisthoff, MD; James R. Gossage, MD; Adrienne Hammill, MD; Ketil Heimdal, MD;
Katharine Henderson, MS, CGC; Vivek N. Iyer, MD, MPH; Anette D. Kjeldsen, MD; Masaki Komiyama, MD; Kevin Korenblatt, MD;
Jamie McDonald, MS, CGC; Jack McMahon; Justin McWilliams, MD; Mary E. Meek, MD; Meir Mei-Zahav, MD; Scott Olitsky, MD, MBA;
Sara Palmer, PhD; Rose Pantalone, RN; Jay F. Piccirillo, MD; Beth Plahn, RN, MHA; Mary E.M. Porteous, MD; Marco C. Post, MD, PhD;
Ivan Radovanovic, MD; Paul J. Rochon, MD; Josanna Rodriguez-Lopez, MD; Carlo Sabba, MD; Marcelo Serra, MD; Claire Shovlin, PhD, MA;
Dennis Sprecher, MD; Andrew J. White, MD; Ingrid Winship, MBChB, MD; and Roberto Zarrabeitia, MD

Description: Hereditary hemorrhagic telangiectasia (HHT) is an
autosomal dominant disease with an estimated prevalence of 1
in 5000 that is characterized by the presence of vascular malformations (VMs). These result in chronic bleeding, acute hemorrhage,
and complications from shunting through VMs. The goal of the Second International HHT Guidelines process was to develop
evidence-based consensus guidelines for the management andprevention of HHT-related symptoms and complications.
Methods: The guidelines were developed using the AGREE II(Appraisal of Guidelines for Research and Evaluation II) framework and GRADE (Grading of Recommendations Assessment,
Development and Evaluation) methodology. The guidelines expert panel included expert physicians (clinical and genetic) in
HHT from 15 countries, guidelines methodologists, health care
workers, health care administrators, patient advocacy representatives, and persons with HHT. During the preconference process, the expert panel generated clinically relevant questions in 6priority topic areas. A systematic literature search was done inHereditary hemorrhagic telangiectasia (HHT) is an
autosomal dominant disease with an estimatedprevalence of approximately 1 in 5000 (1). It is characterized by clinically signiﬁcant vascular malformations(VMs) of skin and mucous membranes of the nose andgastrointestinal (GI) tract as well as the brain, lung, andliver. It is underdiagnosed, and a long diagnostic delay
is common (2). A diagnosis of HHT allows appropriate
screening and preventive treatment to be undertaken
in a patient and their affected family members. The
most common symptom of HHT, epistaxis, has an agerelated expression, as does the appearance of the typical telangiectasia (3). Consensus clinical diagnostic criteria known as the Curaçao criteria were published in2000 (4) (Table 1 of Supplement 1, available at Annals.org) and upheld in the ﬁrst International HHT Guidelines(5). The ﬁrst guidelines also recommended genetic testing for HHT diagnosis, primarily for asymptomatic persons from a family with known HHT, as detailed in the
Table. In 97% of patients with a deﬁnite clinical diagnosis
of HHT, a causative mutation is identiﬁed in one of thesegenes: endoglin (ENG, HHT type 1), activin receptor-likekinase-1 (ACVRL1, HHT type 2), and Mothers against decapentaplegic homolog 4 (SMAD4, juvenile polyposis–
HHT overlap) (6).
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June 2019, and articles meeting a priori criteria were included togenerate evidence tables, which were used as the basis for recommendation development. The expert panel subsequently
convened during a guidelines conference to conduct a structured consensus process, during which recommendations reaching at least 80% consensus were discussed and approved.
Recommendations: The expert panel generated and approved
6 new recommendations for each of the following 6 priority topic
areas: epistaxis, gastrointestinal bleeding, anemia and iron deﬁciency, liver VMs, pediatric care, and pregnancy and delivery (36total). The recommendations highlight new evidence in existing
topics from the ﬁrst International HHT Guidelines and provide guidance in 3 new areas: anemia, pediatrics, and pregnancy and delivery. These recommendations should facilitate implementation of
key components of HHT care into clinical practice.
Ann Intern Med. doi:10.7326/M20-1443
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For author, article, and disclosure information, see end of text.
This article was published at Annals.org on 8 September 2020.

The goal of this Second International HHT Guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT, prevention of HHT-related complications, and treatment ofsymptomatic disease in areas not previously addressedby guidelines and those where signiﬁcant new literature had been published. Several other recommendations from the ﬁrst International HHT Guidelines were
not reassessed during this process and remain currently recommended (Table).

METHODSThe Second International HHT Guidelines were developed using the AGREE II (Appraisal of Guidelines for

See also:
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CLINICAL GUIDELINE
Table. Clinical Recommendations From the Second
International HHT Guidelines and Currently
Recommended Clinical Recommendations From the FirstInternational HHT Guidelines*
Listed here are the clinical recommendations with ≥80% consensus at theSecond International HHT Guidelines conference. These are followedby the clinical recommendations from the ﬁrst International Guidelinesthat had ≥80% consensus and were not reassessed by the 2019
International Guidelines Working Group. The expert panel is aware of
new evidence and insights regarding some of these existing guidelines,
and they have been prioritized for updating in the next guidelines
process (Part 4 of Supplement 2, available at Annals.org).
Epistaxis management
A1: The expert panel recommends that patients with HHT-related epistaxis
use moisturizing topical therapies that humidify the nasal mucosa to
reduce epistaxis.*
Quality of evidence: moderate (agreement, 98%)
Strength of recommendation: strong (agreement, 100%)
A2: The expert panel recommends that clinicians consider the use of oral
tranexamic acid for the management of epistaxis that does not respondto moisturizing topical therapies.*
Quality of evidence: high (agreement, 92%)
Strength of recommendation: strong (agreement, 94%)
A3: The expert panel recommends that clinicians should consider ablative
therapies for nasal telangiectasias, including laser treatment,
radiofrequency ablation, electrosurgery, and sclerotherapy, in patientsthat have failed to respond to moisturizing topical therapies.*
Quality of evidence: moderate (agreement, 83%)
Strength of recommendation: weak (agreement, 94%)
A4: The expert panel recommends that clinicians consider the use of systemic
antiangiogenic agents for the management of epistaxis that has failed torespond to moisturizing topical therapies, ablative therapies, and/or
tranexamic acid.*
Quality of evidence: moderate (agreement, 92%)
Strength of recommendation: strong (agreement, 82%)
A5: The expert panel recommends that clinicians consider aseptodermoplasty for patients whose epistaxis has failed to respond
sufﬁciently to moisturizing topical therapies, ablative therapies, and/or
tranexamic acid.*
Quality of evidence: low (agreement, 92%)
Strength of recommendation: weak (agreement, 88%)
A6: The expert panel recommends that clinicians consider a nasal closure forpatients whose epistaxis has failed to respond sufﬁciently to moisturizing
topical therapies, ablative therapies, and/or tranexamic acid.*
Quality of evidence: moderate (agreement, 86%)
Strength of recommendation: strong (agreement, 82%)
A7: The expert panel recommends that physicians advise patients with
HHT-related epistaxis to use agents that humidify the nasal mucosa toprevent epistaxis. (Agreement, 94%)†
Level of evidence: III
Strength of recommendation: weak
A8: The expert panel recommends that clinicians refer HHT patients withepistaxis and who desire treatment to otorhinolaryngologists with HHT
expertise for evaluation and treatment. (Agreement, 87%)†
Level of evidence: III
Strength of recommendation: weak
A9: The expert panel recommends that when considering nasal surgery forreasons other than epistaxis, the patient and clinician obtain consultationfrom an otorhinolaryngologist with expertise in HHT-related epistaxis.
(Agreement, 100%)†
Level of evidence: III
Strength of recommendation: weakA10: The expert panel recommends that the treatment for acute epistaxis
requiring intervention include packing with material or products thathave a low likelihood of causing rebleeding with removal (e.g.,
lubricated low-pressure pneumatic packing). (Agreement, 93%)†
Level of evidence: III
Strength of recommendation: weakInternational HHT Guidelines

Table—Continued
GI bleeding management*
B1: The expert panel recommends esophagogastroduodenoscopy as theﬁrst-line diagnostic test for suspected HHT-related bleeding. Patients
who meet colorectal cancer screening criteria and patients with
SMAD4-HHT (genetically proven or suspected) should also undergo
colonoscopy.
Quality of evidence: low (agreement, 82%)
Strength of recommendation: strong (agreement, 94%)
B2: The expert panel recommends considering capsule endoscopy forsuspected HHT-related bleeding when esophagogastroduodenoscopy
does not reveal signiﬁcant HHT-related telangiectasia.
Quality of evidence: low (agreement, 92%)
Strength of recommendation: strong (agreement, 88%)
B3: The expert panel recommends that clinicians grade the severity of
HHT-related GI bleeding and proposes the following framework:• Mild HHT-related GI bleeding: patient who meets their hemoglobin
goals‡ with oral iron replacement• Moderate HHT-related GI bleeding: patient who meets their hemoglobin
goals‡ with intravenous iron treatment• Severe HHT-related GI bleeding: patient who does not meet theirhemoglobin goals‡ despite adequate iron replacement or requires
blood transfusions
Quality of evidence: low (expert consensus) (agreement, 96%)
Strength of recommendation: strong (agreement, 96%)
B4: The expert panel recommends that endoscopic argon plasma
coagulation be only used sparingly during endoscopy.
Quality of evidence: low (expert consensus) (agreement, 88%)
Strength of recommendation: weak (agreement, 81%)
B5: The expert panel recommends that clinicians consider treatment of mild
HHT-related GI bleeding with oral antiﬁbrinolytics.
Quality of evidence: low (agreement, 94%)
Strength of recommendation: weak (agreement, 90%)
B6: The expert panel recommends that clinicians consider treatment ofmoderate to severe HHT-related GI bleeding with intravenous
bevacizumab or other systemic antiangiogenic therapy.
Quality of evidence: moderate (agreement, 94%)
Strength of recommendation: strong (agreement, 98%)
Anemia and anticoagulation*
C1: The expert panel recommends that the following HHT patients be tested
for iron deﬁciency and anemia:• All adults, regardless of symptoms• All children with recurrent bleeding and/or symptoms of anemia
Quality of evidence: high (agreement, 98%)
Strength of recommendation: strong (agreement, 96%)
C2: The expert panel recommends iron replacement for treatment of irondeﬁciency and anemia as follows:• Initial therapy with oral iron
• Intravenous iron replacement for patients in whom oral is not effective, notabsorbed, or not tolerated, or who are presenting with severe anemia
Quality of evidence: moderate (agreement, 88%)
Strength of recommendation: strong (agreement, 100%)
C3: The expert panel recommends red blood cell transfusions in thefollowing settings:• Hemodynamic instability/shock• Comorbidities that require a higher hemoglobin target• Need to increase the hemoglobin acutely, such as prior to surgery or
during pregnancy• Inability to maintain an adequate hemoglobin despite frequent ironinfusions
Quality of evidence: low (agreement, 92%)
Strength of recommendation: strong (agreement, 96%)
C4: The expert panel recommends considering evaluation for additionalcauses of anemia in the setting of an inadequate response to ironreplacement.
Quality of evidence: low (agreement, 100%)Strength of recommendation: strong (agreement, 100%)
C5: The expert panel recommends that HHT patients receive anticoagulation(prophylactic or therapeutic) or antiplatelet therapy when there is anindication, with consideration of their individualized bleeding risks;
bleeding in HHT is not an absolute contraindication for these therapies.

Continued on following page2 Annals of Internal Medicine

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CLINICAL GUIDELINEInternational HHT Guidelines

Table—Continued
Quality of evidence: low (agreement, 98%)
Strength of recommendation: strong (agreement, 98%)
C6: The panel recommends avoiding the use of dual antiplatelet therapy
and/or combination of antiplatelet therapy and anticoagulation, where
possible, in patients with HHT.
Quality of evidence: low (expert consensus) (agreement, 83%)
Strength of recommendation: weak (agreement, 92%)

Table—Continued
E4: The expert panel recommends repeating pulmonary AVM screening inasymptomatic children with HHT or at risk for HHT, typically at 5-year
intervals.
Quality of evidence: low (agreement, 92%)
Strength of recommendation: strong (agreement, 86%)
E5: The expert panel recommends screening for brain VM in asymptomaticchildren with HHT or at risk for HHT, at the time of presentation/
diagnosis.
Quality of evidence: low (agreement, 86%)
Strength of recommendation: strong (agreement, 86%)
E6: The expert panel recommends that brain VMs with high-risk features betreated.
Quality of evidence: low (agreement, 100%)Strength of recommendation: strong (agreement, 98%)

Liver VMs in HHT
D1: The expert panel recommends that screening for liver VMs be offered toadults with deﬁnite or suspected HHT.*
Quality of evidence: low (agreement, 84%)
Strength of recommendation: weak (agreement, 93%)
D2: The expert panel recommends diagnostic testing for liver VMs in HHT
patients with symptoms and/or signs suggestive of complicated liver
VMs (including heart failure, pulmonary hypertension, abnormal cardiac
biomarkers, abnormal liver function tests, abdominal pain, portal
hypertension, or encephalopathy), using Doppler ultrasound,multiphase contrast CT scan, or contrast abdominal MRI for diagnostic
assessment of liver VMs.*
Quality of evidence: high (agreement, 98%)
Strength of recommendation: strong (agreement, 100%)
D3: The expert panel recommends an intensive ﬁrst-line management only
for patients with complicated and/or symptomatic liver VMs, tailored tothe type of liver VM complication(s).
The expert panel recommends that HHT patients with high-output cardiac
failure and pulmonary hypertension be comanaged by the HHT Centerof Excellence and an HHT cardiologist or a pulmonary hypertension
specialty clinic.*
Quality of evidence: moderate (agreement, 88%)
Strength of recommendation: strong (agreement, 88%)
D4: The expert panel recommends that clinicians estimate prognosis of liver
VMs using available predictors, to identify patients in need of closer
monitoring.*
Quality of evidence: moderate (agreement, 89%)
Strength of recommendation: strong (agreement, 82%)
D5: The expert panel recommends considering intravenous bevacizumab forpatients with symptomatic high-output cardiac failure due to liver VMs
who have failed to respond sufﬁciently to ﬁrst-line management.*
Quality of evidence: moderate (agreement, 98%)
Strength of recommendation: strong (agreement, 98%)
D6: The expert panel recommends referral for consideration of livertransplantation for patients with symptomatic complications of liver VMs,
speciﬁcally refractory high-output cardiac failure, biliary ischemia, orcomplicated portal hypertension.*
Quality of evidence: moderate (agreement, 83%)
Strength of recommendation: strong (agreement, 92%)
D7: The expert panel recommends that liver biopsy be avoided in any patientwith proven or suspected HHT. (Agreement, 97%)†
Level of evidence: III
Strength of recommendation: strong
D8: The expert panel recommends that hepatic artery embolization be
avoided in patients with liver VMs as it is only a temporizing procedureassociated with signiﬁcant morbidity and mortality. (Agreement, 94%)†
Level of evidence: III
Strength of recommendation: strong

Pregnancy and delivery*
F1: The expert panel recommends that clinicians discuss preconception andprenatal diagnostic options, including preimplantation genetic
diagnosis, with HHT-affected individuals.
Quality of evidence: very low (agreement, 86%)
Strength of recommendation: strong (agreement, 83%)
F2: The expert panel recommends testing with unenhanced MRI in pregnant
women with symptoms suggestive of brain VMs.
Quality of evidence: very low (agreement, 98%)
Strength of recommendation: strong (agreement, 92%)
F3: The expert panel recommends that pregnant women with HHT who havenot been recently screened and/or treated for pulmonary AVM should
be approached as follows:• In asymptomatic patients, initial pulmonary AVM screening should be
performed using either agitated saline transthoracic contrast
echocardiography (TTCE) or low-dose noncontrast chest CT, dependingon local expertise. Chest CT, when performed, should be done early inthe second trimester.
• In patients with symptoms suggestive of pulmonary AVM, diagnostic
testing should be performed using low-dose noncontrast chest CT. This
testing can be performed at any gestational age, as clinically indicated.
• Pulmonary AVMs should be treated starting in the second trimester
unless otherwise clinically indicated.
Quality of evidence: moderate (agreement, 88%)
Strength of recommendation: strong (agreement, 83%)
F4: The expert panel recommends that pregnant women with HHT be
managed at a tertiary care center by a multidisciplinary team if they have
untreated pulmonary AVMs and/or brain VMs or have not been recently
screened for pulmonary AVMs.
Quality of evidence: very low (agreement, 94%)
Strength of recommendation: strong (agreement, 85%)
F5: The expert panel recommends not withholding an epidural because of adiagnosis of HHT, and that screening for spinal vascular malformations is
not required.
Quality of evidence: low (agreement, 98%)
Strength of the recommendation: strong (agreement, 92%)
F6: The expert panel recommends that women with known, non–high-riskbrain VMs can labor and proceed with vaginal delivery. Patients may
require an assisted second stage on a case-by-case basis.
Quality of evidence: moderate (agreement, 94%)
Strength of the recommendation: strong (agreement, 94%)

Pediatric care*
E1: The expert panel advises that diagnostic genetic testing be offered forasymptomatic children of a parent with HHT.
Quality of evidence: high (agreement, 96%)
Strength of recommendation: strong (agreement, 94%)
E2: The expert panel recommends screening for pulmonary AVMs inasymptomatic children with HHT or at risk for HHT at the time ofpresentation/diagnosis.
Quality of evidence: moderate (agreement, 94%)
Strength of recommendation: strong (agreement, 94%)
E3: The expert panel recommends that large pulmonary AVMs andpulmonary AVMs associated with reduced oxygen saturation be treatedin children to avoid serious complications.
Quality of evidence: moderate (agreement, 98%)
Strength of recommendation: strong (agreement, 98%)

Diagnosis of HHT†
G1: The expert panel recommends that clinicians diagnose HHT using the
Curaçao criteria or by identiﬁcation of a causative mutation. (Agreement,
82%)
Level of evidence: III
Strength of recommendation: weak
G2: The expert panel recommends that clinicians consider the diagnosis of
HHT in patients with one or more Curaçao criteria. (Agreement, 91%)
Level of evidence: III
Strength of recommendation: weak
G3: The expert panel recommends that asymptomatic children of a parent
with HHT be considered to have possible HHT, unless excluded bygenetic testing. (Agreement, 87%)
Level of evidence: III
Strength of recommendation: weakContinued on following page
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3CLINICAL GUIDELINE
Table—Continued
G4: The expert panel recommends that clinicians refer patients for diagnostic
genetic testing for HHT (Agreement, 80%)
1. to identify the causative mutation in a family with clinically conﬁrmed
HHT;
2. to establish a diagnosis in relatives of a person with a known causative
mutation, including
a. individuals who are asymptomatic or minimally symptomatic andb. individuals who desire prenatal testing; and3. to assist in establishing a diagnosis of HHT in individuals who do notmeet clinical diagnostic criteria.
Level of evidence: III
Strength of recommendation: weak
G5: The expert panel recommends that for individuals who test negative for
ENG and ACVRL1 coding sequence mutations, SMAD4 testing should
be considered to identify the causative mutation. (Agreement, 93%)
Level of evidence: III
Strength of recommendation: weakBrain VMs†
H1: The expert panel recommends the use of MRI for brain VM screening in
adults with possible or deﬁnite HHT using a protocol with and without
contrast administration and using sequences that detect blood products,
to maximize sensitivity. (Agreement, 100%)Level of evidence: III
Strength of recommendation: weak
H2: The expert panel recommends that adults presenting with an acutehemorrhage secondary to a brain VM be considered for deﬁnitive
treatment in a center with neurovascular expertise. (Agreement, 94%)
Level of evidence: III
Strength of recommendation: strong
H3: The expert panel recommends that all other adults with brain VMs bereferred to a center with neurovascular expertise to be considered forinvasive testing and individualized management. (Agreement, 84%)
Level of evidence: III
Strength of recommendation: strong
H4: The expert panel recommends that pregnant women with suspected or
conﬁrmed HHT harboring an asymptomatic brain VM during pregnancy
have deﬁnitive treatment of their brain VM deferred until after delivery of
their fetus. The expert panel recommends that the delivery of the fetus
follow obstetrical principles. (Agreement, 80%)
Level of evidence: III
Strength of recommendation: weakPulmonary AVMs†
I1: The expert panel recommends that clinicians screen all patients withpossible or conﬁrmed HHT for pulmonary AVMs. (Agreement, 96%)
Level of evidence: III
Strength of recommendation: strong
I2: The expert panel recommends that clinicians use transthoracic contrast
echocardiography as the initial screening test for pulmonary AVM.
(Agreement, 96%)
Level of evidence: II
Strength of recommendation: weak
I3: The expert panel recommends that clinicians treat pulmonary AVMs withtranscatheter embolotherapy. (Agreement, 96%)
Level of evidence: II
Strength of recommendation: strong
I4: The expert panel recommends that clinicians provide the following
long-term advice to patients with documented pulmonary AVMs (treatedor untreated):
1. Antibiotic prophylaxis for procedures with risk of bacteremia
2. When IV access is in place, take extra care to avoid IV air
3. Avoidance of SCUBA diving (Agreement, 87%)
Level of evidence: III
Strength of recommendation: weak
I5: The expert panel recommends that clinicians provide long-term follow-up
for patients who have pulmonary AVMs, in order to detect growth of
untreated pulmonary AVMs and also reperfusion of treated AVMs.
(Agreement, 100%)

4 Annals of Internal Medicine

International HHT Guidelines

Table—Continued
Level of evidence: II
Strength of recommendation: strong

AVM = arteriovenous malformation; CT = computed tomography;
EGD = esophagogastroduodenoscopy; GI = gastrointestinal; HHT =hereditary hemorrhagic telangiectasia; IV = intravenous; MRI = magnetic resonance imaging; VM = vascular malformation.
* Second HHT Guidelines.
† First HHT Guidelines.
‡ Hemoglobin goals should reﬂect age, gender, symptoms, andcomorbidities.

Research and Evaluation II) framework and GRADE(Grading of Recommendations Assessment, Development and Evaluation) methodology. The international
HHT community provided priority topics to be updated
on the basis of new evidence or added because notpreviously addressed. The Table details recommendations that were not revisited but are still currently recommended. Topic groups were appointed for each of
the 6 areas selected for update or new review. They
identiﬁed key questions to guide the systematic searchstrategy of the literature. A medical librarian (K.L.R.) developed and executed 6 sets of search strategies between May and June 2019 in Ovid MEDLINE with input
from the chair of the Guidelines Working Group(GWG). Through a series of predetermined steps illustrated in Part 1 of Supplement 2 (available at Annals.org), including double review of both abstracts andfull-text articles, 221 articles were summarized into evidence tables. The quality of included randomized controlled trials (RCTs) was assessed (Part 2 of Supplement
2) using the structured framework of the Cochrane Riskof Bias Tool (7). In the months preceding the conference, the 6 topic groups generated draft recommendations that were based on key questions and the evidence tables and were consistent with GRADE (8)formatting for levels of evidence and strength of recommendation. Draft recommendations were distributed to all panel members 2 weeks before the consensus meeting.
The GWG convened at the guidelines conferencein November 2019 in Toronto, Canada, to partake in a
structured consensus process. The GWG included clinical and genetic experts in all aspects of HHT from 15
countries, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical
trainees, patient advocacy representatives, and patientswith HHT. The GWG completed individual conﬂict-ofinterest disclosures, and the chair reviewed potential
conﬂicts. The GWG was presented draft recommendations with supporting quality of evidence, voted anonymously on the wording and quality of evidence, waspresented the draft strength of recommendation withjustiﬁcation by GRADE methodology, and then votedon the strength of recommendation. Consensus of 80%
was required for the recommendation to be included in
the guidelines. A structured process was used to identify sources of disagreement for votes with less than
80% agreement (Supplement 1). The recommendations were sent for external review to HHT experts andorganizations; their comments were collated and adAnnals.org

International HHT Guidelines

dressed (Part 3 of Supplement 2). The funding sources
had no role in the design, conduct, or reporting of theguidelines or in the decision to submit for publication.
Although the funding sources were not directly involved in the generation of the recommendations,some participants in the guidelines process were alsoboard members, ofﬁcers, or committee members ofCure HHT.

RECOMMENDATIONS
A summary of all the recomendations is available in
the Table.
Epistaxis Management
Recommendation A1: The expert panel recommends that patients with HHT-related epistaxis use
moisturizing topical therapies that humidify the nasal
mucosa to reduce epistaxis. (Quality of evidence: moderate [agreement, 98%])
Topical saline has been shown to reduce epistaxis
severity score compared with baseline in an RCT of topical therapies (9) (Table 2 of Supplement 1). (Strength ofrecommendation: strong [agreement, 100%])
Clinical considerations: Topical saline (spray or gel)is typically used twice daily.
Recommendation A2: The expert panel recommends
that clinicians consider the use of oral tranexamic acid forthe management of epistaxis that does not respond tomoisturizing topical therapies. (Quality of evidence: high[agreement, 92%])
Two RCTs of oral tranexamic acid showed a significant decrease in epistaxis severity (10, 11) with minimal
adverse events (Table 2 of Supplement 1). (Strength ofrecommendation: strong [agreement, 94%])
Clinical considerations: Table 4 of Supplement 1
gives prescribing and safety monitoring guidance fororal tranexamic acid.
Recommendation A3: The expert panel recommends that clinicians should consider ablative therapies
for nasal telangiectasias, including laser treatment, radiofrequency ablation, electrosurgery, and sclerotherapy, in patients that have failed to respond to moisturizing topical therapies. (Quality of evidence: moderate[agreement, 83%])
One RCT showed reduced epistaxis severity scorewith sclerotherapy (12). Multiple uncontrolled series
demonstrated that various ablative therapies temporarily
reduced epistaxis (13–15) (Tables 2 and 3 of Supplement1). (Strength of recommendation: weak [agreement,
94%])
Clinical considerations: Clinicians and patientsshould choose a speciﬁc ablative therapy on the basisof local expertise, understanding that ablative therapy
is a temporizing treatment of epistaxis and that perforation of the nasal septum is a known complication of
all techniques.
Recommendation A4: The expert panel recommends that clinicians consider the use of systemic antiangiogenic agents for the management of epistaxis thathas failed to respond to moisturizing topical therapies,
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CLINICAL GUIDELINE
ablative therapies, and/or tranexamic acid. (Quality ofevidence: moderate [agreement, 92%])
Multiple uncontrolled series demonstrated that
intravenous (IV) bevacizumab reduced epistaxis, improved anemia, reduced transfusion requirements, or
improved quality of life (QOL) (16 –23) (Table 3 of Supplement 1). (Strength of recommendation: strong[agreement, 82%])
Clinical considerations: Table 4 of Supplement 1
gives prescribing and safety monitoring guidance for IV
bevacizumab.
Recommendation A5: The expert panel recommends that clinicians consider a septodermoplasty forpatients whose epistaxis has failed to respond sufﬁciently to moisturizing topical therapies, ablative therapies, and/or tranexamic acid. (Quality of evidence: low[agreement, 92%])
Multiple uncontrolled series demonstrated that
septodermoplasty reduced epistaxis, improved anemia, reduced surgical reintervention, or improved QOL(24 –29) (Table 3 of Supplement 1). (Strength of recommendation: weak [agreement, 88%])
Clinical considerations: Clinicians and patientsshould consider septodermoplasty when epistaxis affects QOL or is life-threatening; they should consider
the risks and beneﬁts, as well as alternatives, such as
nasal closure and antiangiogenic medications.
Recommendation A6: The expert panel recommends that clinicians consider a nasal closure for patients whose epistaxis has failed to respond sufﬁciently
to moisturizing topical therapies, ablative therapies,
and/or tranexamic acid. (Quality of evidence: moderate[agreement, 86%])
Multiple uncontrolled series demonstrated that nasal
closure reduced epistaxis (26, 28) (Table 3 of Supplement1). (Strength of recommendation: strong [agreement,
82%])
Clinical considerations: Clinicians and patientsshould consider nasal closure when epistaxis affects
QOL or is life-threatening; they should consider therisks and beneﬁts, as well as alternatives, such as septodermoplasty and antiangiogenic medications.
GI Bleeding Management
Recommendation B1: The expert panel recommends esophagogastroduodenoscopy as the ﬁrst-line
diagnostic test for suspected HHT-related bleeding. Patients who meet colorectal cancer screening criteria andpatients with SMAD4-HHT (genetically proven or suspected) should also undergo colonoscopy. (Quality ofevidence: low [agreement, 82%])
Several cross-sectional studies of diagnostic yielddemonstrated a high yield from esophagogastroduodenoscopy (EGD) for upper GI telangiectases in patients with HHT and suspected GI bleeding (30 –32)
(Table 5 of Supplement 1). (Strength of recommendation: strong [agreement, 94%])
Clinical considerations: Clinicians should consider
performing EGD in an experienced center given potential unusual complications during the procedure (suchas massive epistaxis) and should also be aware of theAnnals of Internal Medicine

5CLINICAL GUIDELINE
precautions required for patients with HHT and pulmonary arteriovenous malformations (AVMs) (Table).
In suspected or proven SMAD4-HHT, screeningcolonoscopy is recommended starting at age 15 years
and repeated every 3 years if no polyps are found or
every year along with EGD if colonic polyps are found.
Other patients with HHT (non-SMAD4) should bescreened for colon cancer following general population guidelines.
Recommendation B2: The expert panel recommends considering capsule endoscopy for suspected
HHT-related bleeding when esophagogastroduodenoscopy does not reveal signiﬁcant HHT-related telangiectasia. (Quality of evidence: low [agreement, 92%])
Several cross-sectional studies of diagnostic yielddemonstrated a high yield from capsule endoscopy,
with an excellent safety proﬁle, for small-bowel GI telangiectases in patients with HHT and suspected GI
bleeding (30 –34) (Table 5 of Supplement 1). (Strengthof recommendation: strong [agreement, 88%])
Clinical considerations: Capsule endoscopy remains complementary to EGD when anemia is unexplained by the severity of epistaxis and gastric involvement or when the EGD ﬁndings are negative.
Recommendation B3: The expert panel recommends that clinicians grade the severity of HHT-related
GI bleeding and proposes the following framework:• Mild HHT-related GI bleeding: patient who meets
their hemoglobin goals* with oral iron replacement• Moderate HHT-related GI bleeding: patient whomeets their hemoglobin goals* with intravenous
iron treatment• Severe HHT-related GI bleeding: patient who
does not meet their hemoglobin goals* despite
adequate iron replacement or requires bloodtransfusions* Hemoglobin goals should reﬂect age, gender,
symptoms, and comorbidities. (Quality of evidence: low[expert consensus] [agreement, 96%])
Case series describe a severity range for HHTrelated GI bleeding, with secondary anemia, reduced
QOL, blood transfusion requirements, hospitalization,
morbidity, and mortality (32, 35– 41). (Strength of recommendation: strong [agreement, 96%])
Clinical considerations: Hemoglobin goals (not levels) are speciﬁed to reﬂect the patient's individual physiologic needs. This classiﬁcation applies to patients
who have had at least 3 months of iron therapy.
Recommendation B4: The expert panel recommends that endoscopic argon plasma coagulation be
only used sparingly during endoscopy. (Quality of evidence: low [expert consensus] [agreement, 88%])
Expert consensus in HHT and case series in patients without HHT show some beneﬁt from endoscopic
argon plasma coagulation (42, 43). (Strength of recommendation: weak [agreement, 81%])
Clinical considerations: Argon plasma coagulation
is best administered concurrent with the initial endoscopic evaluation for bleeding lesions and signiﬁcant
6 Annals of Internal Medicine

International HHT Guidelines(1- to 3-mm) nonbleeding lesions. Repeated sessions
are discouraged to avoid repeated iatrogenic injury to
the intestinal mucosa.
Recommendation B5: The expert panel recommends that clinicians consider treatment of mild HHTrelated GI bleeding with oral antiﬁbrinolytics. (Quality ofevidence: low [agreement, 94%])
One case series reported reduced need for endoscopic management in patients treated with oral
tranexamic acid (44) (Table 6 of Supplement 1) with agood safety proﬁle. (Strength of recommendation:
weak [agreement, 90%])
Clinical considerations: Table 4 of Supplement 1
gives prescribing and safety monitoring guidance fororal tranexamic acid.
Recommendation B6: The expert panel recommends that clinicians consider treatment of moderate tosevere HHT-related GI bleeding with intravenous bevacizumab or other systemic antiangiogenic therapy.
(Quality of evidence: moderate [agreement, 94%])
Small uncontrolled series showed that systemic antiangiogenic therapies alleviated anemia, reduced
transfusion requirements, or improved QOL (19, 21,45) (Table 6 of Supplement 1). (Strength of recommendation: strong [agreement, 98%])
Clinical considerations: Table 4 of Supplement 1
gives prescribing and safety monitoring guidance for IV
bevacizumab.
Anemia and Anticoagulation
Recommendation C1: The expert panel recommends that the following HHT patients be tested for irondeﬁciency and anemia:• All adults, regardless of symptoms• All children with recurrent bleeding and/or symptoms of anemia (Quality of evidence: high [agreement, 98%])
Three case series reported iron deﬁciency anemia
as a common complication of HHT, typically in adults(36, 46, 47). (Strength of recommendation: strong[agreement, 96%])
Clinical considerations: Testing typically includes
complete blood count and ferritin measurement. If apatient is anemic but ferritin is not reduced, serum iron,
total iron-binding capacity, and transferrin saturation
should be measured and a hematology consultation
should be considered.
Recommendation C2: The expert panel recommends iron replacement for treatment of iron deﬁciency
and anemia as follows:• Initial therapy with oral iron
• Intravenous iron replacement for patients inwhom oral is not effective, not absorbed, or not
tolerated, or who are presenting with severe anemia (Quality of evidence: moderate [agreement,
88%])
Evidence for iron replacement and initial dosing
are based on case series in HHT and non-HHT iron deﬁciency anemia (48 –53). (Strength of recommendation:strong [agreement, 100%])
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International HHT Guidelines

Clinical considerations: Iron replacement typicallystarts with once-daily oral dosing of 35 to 65 mg ofelemental iron, 2 hours before or 1 hour after meals. An
increase in hemoglobin of less than 10 g/L is considered inadequate in anemic patients, and every-otherday dosing or an alternate preparation of oral ironshould be attempted. In refractory anemia or severe
chronic bleeding, regularly scheduled iron infusions may
be required. Initial IV iron dosing can be calculated (54),or a total initial dose of 1 g of IV iron can be provided, asa single infusion or divided doses. Supplement 1 details
additional safety and prescribing information.
Recommendation C3: The expert panel recommends
red blood cell transfusions in the following settings:• Hemodynamic instability/shock• Comorbidities that require a higher hemoglobin
target• Need to increase the hemoglobin acutely, such asprior to surgery or during pregnancy• Inability to maintain an adequate hemoglobin despite frequent iron infusions (Quality of evidence:
low [agreement, 92%])
Expert consensus in HHT. (Strength of recommendation: strong [agreement, 96%])
Clinical considerations: Hemoglobin targets andthresholds for red blood cell transfusion should be individualized in HHT, depending on patient symptoms,
severity of ongoing HHT-related bleeding, response toother therapies and iron supplementation, presence ofcomorbid conditions, and acuity.
Recommendation C4: The expert panel recommends considering evaluation for additional causes ofanemia in the setting of an inadequate response to ironreplacement. (Quality of evidence: low [agreement,
100%])
One case series reported folate deﬁciency and hemolysis as additional causes of anemia in patients with
HHT (55). (Strength of recommendation: strong [agreement, 100%])
Clinical considerations: Evaluation should include
measurement of folate, vitamin B12, mean corpuscularvolume, and thyroid-stimulating hormone; smear; reticulocyte counts; and work-up for hemolysis, with referral to hematology in unresolved cases.
Recommendation C5: The expert panel recommends that HHT patients receive anticoagulation (prophylactic or therapeutic) or antiplatelet therapy when
there is an indication, with consideration of their individualized bleeding risks; bleeding in HHT is not an absolute contraindication for these therapies. (Quality of evidence: low [agreement, 98%])
Expert consensus in HHT and 2 case series demonstrated that anticoagulation or antiplatelet therapy iswell tolerated by most patients with HHT (56, 57).
(Strength of recommendation: strong [agreement,
98%])
Clinical considerations: When anticoagulation ispursued, unfractionated heparin, low-molecular-weight
heparin, and vitamin K antagonists are preferred overdirect-acting oral anticoagulants, which are less wellAnnals.org

CLINICAL GUIDELINE
tolerated in HHT (58). In cases of atrial ﬁbrillation, if
anticoagulation is not tolerated, alternate approaches
can be considered, such as left atrial appendage
closure (59).
Recommendation C6: The panel recommends
avoiding the use of dual antiplatelet therapy and/or
combination of antiplatelet therapy and anticoagulation, where possible, in patients with HHT. (Quality ofevidence: low (expert consensus) [agreement, 83%])
Expert consensus in HHT. (Strength of recommendation: weak [agreement, 92%])
Clinical considerations: If dual or combination therapies are required, duration of therapy should be minimized and patients should be monitored closely.
Liver VMs in HHT
Recommendation D1: The expert panel recommends that screening for liver VMs be offered to adults
with deﬁnite or suspected HHT. (Quality of evidence:
low [agreement, 84%])
Several cross-sectional diagnostic studies demonstrated high yield and accuracy of Doppler ultrasonography, multiphase contrast computed tomography (CT),and magnetic resonance imaging (MRI) for detection ofliver VMs (5, 60 – 68) (Table 7 of Supplement 1); Doppler
ultrasonography severity grading was predictive of outcomes (69). Anicteric cholestasis, reported in one third ofpatients with liver VMs, correlated with severity of liver
VMs and complications (69 –71). (Strength of recommendation: weak [agreement, 93%])
Clinical considerations: The rationale for screeningis that awareness of liver VMs could improve subsequent patient management or help conﬁrm the diagnosis of HHT. The imaging test of choice is Doppler ultrasonography because of its accuracy, safety, tolerability,
low costs, and operating characteristics. However, depending on local availability of and expertise in Doppler ultrasonography, as well as patient preference, patients may be screened clinically (history, physicalexamination, and blood work) or alternative imaging
may be considered, including multiphase contrast CT
or MRI.
Recommendation D2: The expert panel recommends diagnostic testing for liver VMs in HHT patientswith symptoms and/or signs suggestive of complicatedliver VMs (including heart failure, pulmonary hypertension, abnormal cardiac biomarkers, abnormal liver function tests, abdominal pain, portal hypertension, or encephalopathy), using Doppler ultrasound, multiphase
contrast CT scan, or contrast abdominal MRI for diagnostic assessment of liver VMs. (Quality of evidence:high [agreement, 98%])
Several cross-sectional diagnostic studies demonstrated high yield and accuracy of Doppler ultrasonography, multiphase contrast CT, and MRI for diagnosisof liver VMs (5, 60 – 68) (Table 7 of Supplement 1).
(Strength of recommendation: strong [agreement, 100%])
Clinical considerations: The choice of imaging
method should be informed by the risk– beneﬁt balance, local expertise, and availability or cost. Contrast
studies (CT and MRI) should be avoided if kidney dysAnnals of Internal Medicine

7CLINICAL GUIDELINE
function is present. Echocardiography provides additional information about the hemodynamic effect ofliver VMs. These tests will be most informative when
done in the context of a clinical assessment at an HHT
center of excellence.
Recommendation D3: The expert panel recommends an intensive ﬁrst-line management only for patients with complicated and/or symptomatic liver VMs,
tailored to the type of liver VM complication(s).
The expert panel recommends that HHT patients withhigh-output cardiac failure and pulmonary hypertension
be comanaged by the HHT Center of Excellence and an
HHT cardiologist or a pulmonary hypertension specialty
clinic. (Quality of evidence: moderate [agreement, 88%])
One large series showed moderate response toﬁrst-line therapy tailored to liver VM complication (69).
Expert consensus supported the recommendation for
specialized center management. (Strength of recommendation: strong [agreement, 88%])
Clinical considerations: Supplement 1 describesﬁrst-line therapies, by speciﬁc liver VM complication.
Typically, patients with symptomatic liver VMs are managed by an expert team at an HHT center of excellence,with at least annual follow-up.
Recommendation D4: The expert panel recommends
that clinicians estimate prognosis of liver VMs using available predictors, to identify patients in need of closer monitoring. (Quality of evidence: moderate [agreement, 89%])
Three observational studies identiﬁed clinical predictors of complications from liver VMs (69, 70, 72).
(Strength of recommendation: strong [agreement,
82%])
Clinical considerations: Clinicians should plan monitoring for patients with liver VMs on the basis of estimated prognosis.
Recommendation D5: The expert panel recommends considering intravenous bevacizumab for patients with symptomatic high-output cardiac failure due
to liver VMs who have failed to respond sufﬁciently toﬁrst-line management. (Quality of evidence: moderate[agreement, 98%])
Small uncontrolled series showed that IV bevacizumab improved cardiac output or clinical symptoms in
80% of patients with severe liver VMs, primarily in thosewith high-output cardiac failure (16) (Table 8 of Supplement 1). The adverse event rate was reported at 50 per
100 person-years, including 1 fatal event probably related
to bevacizumab (73). (Strength of recommendation: strong[agreement, 98%])
Table 4 of Supplement 1 gives prescribing andsafety monitoring guidance for IV bevacizumab.
Recommendation D6: The expert panel recommends referral for consideration of liver transplantation
for patients with symptomatic complications of liver
VMs, speciﬁcally refractory high-output cardiac failure,biliary ischemia, or complicated portal hypertension.
(Quality of evidence: moderate [agreement, 83%])
Small uncontrolled series of orthotopic liver transplantation for liver VMs in HHT demonstrated excellent
5- to 10-year survival (82% to 92%) (74, 75) with asymptomatic rare and late recurrence of liver VMs after liver
8 Annals of Internal Medicine

International HHT Guidelinestransplantation (76). (Strength of recommendation:strong [agreement, 92%])
Clinical considerations: Timing for listing a symptomatic patient for orthotopic liver transplantation
should be based on prognostic predictors and the severity of liver VM complications, including pulmonary
hypertension. Liver transplantation can be undertakenin the presence of pulmonary hypertension if pulmonary vascular resistance, estimated by right heart catheterization, is less than 3 Woods units.
Pediatric Care
Recommendation E1: The expert panel advises that
diagnostic genetic testing be offered for asymptomaticchildren of a parent with HHT. (Quality of evidence:high [agreement, 96%])
Two cross-sectional diagnostic studies demonstrated that genetic testing can identify subclinical orpresymptomatic disease in children of HHT families
with known mutation (77–79). (Strength of recommendation: strong [agreement, 94%])
Clinical considerations: An affected family member
should be tested ﬁrst to determine the causative mutation before testing an asymptomatic child who does
not meet the clinical diagnostic criteria for HHT (Curaçao criteria) (4). The beneﬁts of testing, alternatives,pros, and cons should be discussed with children or—as
appropriate—their parents.
Recommendation E2: The expert panel recommends screening for pulmonary AVMs in asymptomaticchildren with HHT or at risk for HHT at the time of presentation/diagnosis. (Quality of evidence: moderate[agreement, 94%])
Several pediatric case series demonstrated a prevalence of pulmonary AVMs similar to that in adults anda risk for life-threatening complications with good outcomes from embolization (80 – 85). Several series havereported 2 sensitive screening protocols in children(86 –90) (Table 9 of Supplement 1). (Strength of recommendation: strong [agreement, 94%])
Clinical considerations: Screening may be performed
with either chest radiography and pulse oximetry or transthoracic contrast echocardiography. Screening with CT is
not recommended, although chest CT remains the conﬁrmatory diagnostic test when screening tests have positiveﬁndings.
Recommendation E3: The expert panel recommends that large pulmonary AVMs and pulmonary
AVMs associated with reduced oxygen saturation betreated in children to avoid serious complications.
(Quality of evidence: moderate [agreement, 98%])
Case series demonstrated that children are at risk
for serious complications from large pulmonary AVMs
(or AVMs causing hypoxemia) (82, 83, 85) and that embolization is safe and effective (85) (Table 10 of Supplement 1). (Strength of recommendation: strong [agreement, 98%])
Clinical considerations: Pulmonary AVMs with feeding arteries at least 3 mm in diameter are suitable for
embolotherapy. Follow-up is indicated to detect recanalization and reperfusion of treated AVMs and growth
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International HHT Guidelinesof small untreated AVMs. Speciﬁc protocols vary
among centers (CT, oximetry, or transthoracic contrast
echocardiography), as do intervals.
Recommendation E4: The expert panel recommends repeating pulmonary AVM screening in asymptomatic children with HHT or at risk for HHT, typically at
5-year intervals. (Quality of evidence: low [agreement,92%])
One case series showed growth of pulmonary
AVMs during childhood (91). (Strength of recommendation: strong [agreement, 86%])
Clinical considerations: Screening is typically repeated every 5 years after negative ﬁndings. In children
with indeterminate or borderline screening results
based on either imaging or oximetry, screening should
be repeated sooner.
Recommendation E5: The expert panel recommends screening for brain VM in asymptomatic children
with HHT or at risk for HHT, at the time of presentation/
diagnosis. (Quality of evidence: low [agreement, 86%])
Case series demonstrated risk for intracranial hemorrhage from brain VMs (92–95) in children; MRI as asensitive screening test (96 –98); and beneﬁts of surgical and endovascular management (99, 100), also withsigniﬁcant risk. (Strength of recommendation: strong[agreement, 86%])
Clinical considerations: First-line screening is MRI(contrast-enhanced is more sensitive) to identify brain
VMs and determine subtype and risk factors for hemorrhage. This typically requires sedation or anesthesia inyoung children. The decision to treat versus observe isbased on risk of treatment versus risk for hemorrhage.
As such, the decision to screen the child should beshared among clinicians, caregivers, and the child(where possible). Clinical practice differs across countries, from screening asymptomatic children with MRI in
infancy to no routine screening of asymptomatic children for brain VMs. Patient representatives felt strongly
that children should be screened for brain VMs andcited anecdotal evidence of disastrous outcomes in unscreened patients.
Recommendation E6: The expert panel recommends that brain VMs with high-risk features be treated.
(Quality of evidence: low [agreement, 100%])
Case series demonstrated risk for intracranial hemorrhage from brain VMs (92–95); identiﬁed high-riskfeatures (95, 101, 102); and showed the beneﬁts of surgical and endovascular management (99, 100), alsowith signiﬁcant risk. (Strength of recommendation:strong [agreement, 98%])
Clinical considerations: Given the need to balance
natural history risk with treatment risk, children with
HHT who have brain VMs should be referred to a centerwith multidisciplinary expertise in neurovascular disease management. Treated brain VMs require close follow-up; the follow-up for small (untreated) brain VMs is
not well deﬁned.
Pregnancy and Delivery
Recommendation F1: The expert panel recommends that clinicians discuss preconception and prenaAnnals.org

CLINICAL GUIDELINE
tal diagnostic options, including preimplantation genetic diagnosis, with HHT-affected individuals. (Qualityof evidence: very low [agreement, 86%])
Expert consensus in HHT. (Strength of recommendation: strong [agreement, 83%])
Clinical considerations: Once the causative familial
mutation is identiﬁed in an affected parent, it can bescreened for in future offspring. Available options, including preimplantation, postconception, and postdelivery testing (Supplement 1), vary internationally. The
discussion will be inﬂuenced by local legislation pertaining to preimplantation diagnosis and termination ofpregnancy.
Recommendation F2: The expert panel recommends testing with unenhanced MRI in pregnant
women with symptoms suggestive of brain VMs. (Quality of evidence: very low [agreement, 98%])
Expert consensus in HHT. (Strength of recommendation: strong [agreement, 92%])
Clinical considerations: For symptomatic patients,
including those with previous cerebral hemorrhage,
MRI without gadolinium should be planned in the second trimester. Asymptomatic patients do not requireroutine screening during pregnancy.
Recommendation F3: The expert panel recommends that pregnant women with HHT who have notbeen recently screened and/or treated for pulmonary
AVM should be approached as follows:• In asymptomatic patients, initial pulmonary AVM
screening should be performed using either agitated saline transthoracic contrast echocardiography (TTCE) or low-dose noncontrast chest CT, depending on local expertise. Chest CT, when
performed, should be done early in the second
trimester.
• In patients with symptoms suggestive of pulmonary AVM, diagnostic testing should be performed using low-dose noncontrast chest CT. This
testing can be performed at any gestational age,as clinically indicated.
• Pulmonary AVMs should be treated starting in thesecond trimester unless otherwise clinically indicated. (Quality of evidence: moderate [agreement, 88%])
Case series demonstrated elevated risk for complications from pulmonary AVMs during pregnancy (103–105) and low risk of imaging and embolization in thesecond trimester (106). (Strength of recommendation:strong [agreement, 83%])
Clinical considerations: Technique for embolizationin pregnant patients should include measures to reduce fetal radiation exposure, including avoidance of
ﬂuoroscopy over the abdomen and pelvis, use of
pulsed or low-dose ﬂuoroscopy, minimization of angiography runs, and use of tight collimation. For both
CT and angiography, abdominal shielding is not helpful and may in fact increase scattered radiation to thefetus.
Recommendation F4: The expert panel recommends that pregnant women with HHT be managed at a
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9CLINICAL GUIDELINEInternational HHT Guidelines

tertiary care center by a multidisciplinary team if they
have untreated pulmonary AVMs and/or brain VMs orhave not been recently screened for pulmonary AVMs.
(Quality of evidence: very low [agreement, 94%])
Expert consensus in HHT. (Strength of recommendation: strong [agreement, 85%])
Clinical considerations: Pregnant women with untreated pulmonary AVMs or brain VMs, as well as those
who have not been screened, should be consideredhigh-risk for hemorrhagic and neurologic complications and be managed accordingly by a high-risk teamwith HHT expertise.
Recommendation F5: The expert panel recommends not withholding an epidural because of a diagnosis of HHT, and that screening for spinal vascular malformations is not required. (Quality of evidence: low[agreement, 98%])
Two case series showed no evidence of hemorrhagic complications from epidural or spinal anesthesia(103, 107). (Strength of recommendation: strong[agreement, 92%])
Clinical considerations: Patients should meet withan anesthetist during the early third trimester to discuss
anesthesia options. The risks for complications fromspinal VMs during epidural anesthesia are unsubstantiated and only theoretical.
Recommendation F6: The expert panel recommends that women with known, non– high-risk brain
VMs can labor and proceed with vaginal delivery. Patients may require an assisted second stage on a caseby-case basis. (Quality of evidence: moderate [agreement, 94%])
Two case series showed no intracranial hemorrhage during delivery from brain VMs in patients with
HHT (103, 107). (Strength of recommendation: strong[agreement, 94%])
Clinical considerations: If a brain VM has not previously ruptured, patients may proceed with method ofdelivery based on obstetric indications and discussion
with their obstetric care provider. Vaginal delivery is
not contraindicated. Patients with “high-risk” brain VMs
should be considered for cesarean section or epidural
to allow passive descent of the presenting part, withconsideration of an assisted second stage. Diligent
management of blood pressure is imperative in thesehigher-risk cases, and obtaining the opinion a multidisciplinary neurovascular team is prudent.

Wisconsin (D.P., P.F.); The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada (F.R.); VA Portland Health Care System and Oregon Health & Science University, Portland, Oregon (M.S.C.); Cure HHT, Monkton,
Maryland (M.C., S.O.); University of Utah Medical Center, Salt
Lake City, Utah (K.J.W., J.M.); Massachusetts General Hospitaland Harvard Medical School, Boston, Massachusetts (H.A.);
Washington University School of Medicine, St. Louis, Missouri(M.C., K.K., J.F.P., A.J.W.); St. Michael's Hospital and Unity
Health Toronto, Toronto, Canada (D.C.); HHT Europe, Rome,
Italy (C.C.); Grace Hospital, Winnipeg, Manitoba, Canada(E.D.); HHT Canada, Spruce Grove, Alberta, Canada (C.D.);
Hospices Civils de Lyon, Femme-Mère-Enfant, Lyon, France(S.D.); University Hospital of Marburg and Phillips University
Marburg, Marburg, Germany (U.G.); Augusta University, Augusta, Georgia (J.R.G.); Cincinnati Children's Hospital andUniversity of Cincinnati, Cincinnati, Ohio (A.H.); Oslo University Hospital, Rikshospitalet, Oslo, Norway (K.H.); Yale University School of Medicine, New Haven, Connecticut (K.H.); Mayo
Clinic, Rochester, Minnesota (V.N.I.); Odense University Hospital, Odense, Denmark (A.D.K.); Osaka City General Hospital,
Osaka, Japan (M.K.); Chester, New Jersey (J.M.); University ofCalifornia, Los Angeles, Los Angeles, California (J.M.); University of Arkansas for Medical Sciences, Little Rock, Arkansas(M.E.M.); Schneider Children's Medical Center of Israel andSackler School of Medicine of Tel Aviv University, Tel Aviv,
Israel (M.M.); Baltimore, Maryland (S.P.); Sioux Falls, South Dakota (B.P.); University of Edinburgh, Edinburgh, Scotland(M.E.P.); St. Antonius Hospital, Nieuwegein, and University
Medical Center Utrecht, Utrecht, the Netherlands (M.C.P.); Toronto Western Hospital and University of Toronto, Toronto,
Ontario, Canada (I.R.); University of Colorado Hospital, Aurora, Colorado (P.J.R.); Massachusetts General Hospital, Boston, Massachusetts (J.R.); University of Bari, Bari, Italy (C.S.);
Hospital Italiano de Buenos Aires, Buenos Aires, Argentina(M.S.); Hammersmith Hospital, London, England (C.S.); Blue
Bell, Pennsylvania (D.S.); Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia (I.W.); andHospital Sierrallana (Servicio Cántabro de Salud), Torrelavega, Spain (R.Z.).

From St. Michael's Hospital, Li Ka Shing Knowledge Institute,and University of Toronto, Toronto, Ontario, Canada (M.E.F.);
St. Antonius Hospital, Nieuwegein, the Netherlands (J.J.M.);
University of California, San Francisco, San Francisco, California (S.W.H., M.C.); University of Toronto, Toronto, Ontario,
Canada (V.A.P.); Centre for Effective Practice, Toronto, Ontario, Canada (K.L.); HHT Reference Center ERN, Ospedale
Maggiore, ASST Crema, Crema, Italy (E.B.); Centre Hospitalierde l’Université de Montréal, Hôtel-Dieu, Montreal, Quebec,
Canada (E.D.); University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina (R.S.K., J.D.); St. Michael's Hospitaland University of Toronto, Toronto, Ontario, Canada (A.L.,
R.P.); Froedtert and Medical College of Wisconsin, Milwaukee,

Financial Support: By the Christopher McMahon Family andCure HHT. Dr. Faughnan is supported by the Nelson Arthur
Hyland Foundation and the Li Ka Shing Knowledge Institute of
St Michael's Hospital.

10 Annals of Internal Medicine

Note: Centers with recognized expertise in the diagnosis andmanagement of HHT can be located at https://curehht.org, thewebsite for Cure HHT, and http://vascern.eu, the website for theEuropean Reference Network for Rare Vascular Diseases.
Acknowledgment: The authors thank Nicole Schaefer andSandy Medeiros for their contributions to guideline development and the guidelines conference.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConﬂictOfInterestForms.do?msNum=M20-1443.
Corresponding Author: Marie E. Faughnan, MD, MSc, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada; e-mail, marie.faughnan@unity
health.to.
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International HHT Guidelines
Current author addresses and author contributions are available at Annals.org.

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CLINICAL GUIDELINE
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12 Annals of Internal Medicine

International HHT Guidelines
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14 Annals of Internal Medicine

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Annals.org

Current Author Addresses: Drs. Faughnan, Palda, and Lausman; Mr. Cortes; and Ms. Pantalone: St. Michael's Hospital,
University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8,
Canada.
Drs. Mager and Post: St. Antonius Hospital, Koekoekslaan 1,
Nieuwegein 3435 CM, the Netherlands.
Dr. Hetts: Department of Neurointerventional Radiology, University of California, San Francisco, 505 Parnassus Avenue,
L-351, San Francisco, CA 94143.
Ms. Lang-Robertson: Centre for Effective Practice, 400 University Avenue, Suite 2100, Toronto, ON M5G 1S5, Canada.
Dr. Buscarini: UOC Gastroenterologia ed Endoscopia Digestiva, Ospedale Maggiore, ASST Crema, Largo Dossena 2,
Crema, 26013 Italy.
Dr. Deslandres: Department of Gastroenterology, CHUM, Hotel Dieu, 1051 Rue Sanguinet, C.02.7013, Montreal, QC H2X
0C1, Canada.
Dr. Kasthuri: Division of Hematology/Oncology, University ofNorth Carolina, Chapel Hill, 116 Manning Drive, CB7035,
8206B Mary Ellen Jones, Chapel Hill, NC 27599.
Dr. Poetker: Department of Otolaryngology, Froedtert andMedical College of Wisconsin, 8701 Watertown Plank Road,
Milwaukee, WI 53226.
Dr. Ratjen: Department of Pediatrics, The Hospital for Sick
Children, 555 University Avenue, Toronto, ON M5G 1X8,
Canada.
Dr. Chesnutt: VA Portland Health Care System, HHT Center of
Excellence, 3710 SW US Veterans Hospital Road, P2IES, Portland, OR 97221.
Ms. Clancy and Dr. Olitsky: Cure HHT, PO Box 329, Monkton,
MD 21111.
Dr. Whitehead: Department of Cardiovascular Medicine andPediatric Cardiology, University of Utah Medical Center, 30
North 1900 South, Room 4A100, Salt Lake City, UT 84132.
Dr. Al-Samkari: Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Zero Emerson Place
Suite 118, Ofﬁce 112, Boston, MA 02114.
Dr. Chakinala: Department of Pulmonology and Critical Care,
Washington University School of Medicine, 660 South Euclid
Avenue, Campus Box 8052, St. Louis, MO 63110.
Dr. Conrad: Zuckerberg San Francisco General Hospital, 1001
Potrero Avenue, San Francisco, CA 94114.
Ms. Crocione: HHT Europe, Via Europa 63, Rome, 05022 Italy.
Dr. Darling: Department of Hepatology, University of North
Carolina, Chapel Hill, 8014 Burnett Womack Building, CB
7584, Chapel Hill, NC 27599.
Dr. de Gussem: Department of Medicine, Section of Respirology, Grace Hospital, 300 Booth Drive, Winnipeg, MB R3J
3M7, Canada.
Dr. Dupuis-Girod: Hospices Civils de Lyon, Femme-MèreEnfant, 59 Boulevard Pinel, 69677 Bron, France.
Dr. Foy: Department of Hematology, Froedtert and Medical
College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226.
Dr. Geisthoff: Department of Otorhinolaryngology, Head andNeck Surgery, University Hospital of Marburg, Phillips University Marburg, Baldingerstraße, 35043 Marburg, Germany.
Dr. Gossage: Augusta University, 1120 Fifteenth Street, BBR5513, Augusta, GA 30912.
Dr. Hammill: Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital, and Department of Pediatrics, University of Cincinnati, 3333 Burnet Avenue, MLC 7015, Cincinnati, OH 45229.
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Dr. Heimdal: Department of Genetics, Oslo University Hospital, Rikshospitalet, PO Box 4950 Nydalen, 4950 Oslo, Norway.
Ms. Henderson: Yale University School of Medicine, PO Box
208042, New Haven, CT 06520.
Dr. Iyer: Division of Pulmonary and Critical Care Medicine,
Mayo Clinic, Rochester, MN 55905.
Dr. Kjeldsen: Department of Otorhinolaryngology Head andNeck Surgery, HHT-center OUH, J.B.Winsløws Vej 4, 5000
Odense, Denmark.
Dr. Komiyama: Department of Neurointervention, Osaka City
General Hospital, 2-13-22, Miyakojima-Hondori, Miyakojima,
Osaka 534-0021, Japan.
Dr. Korenblatt: Department of Hepatology, Washington University School of Medicine, 660 South Euclid Avenue, Campus
Box 8124, St. Louis, MO 63110,
Ms. McDonald: Department of Pathology and Radiology, University of Utah Medical Center, 50 North Medical Drive
4A100, Salt Lake City, UT 84132.
Dr. McWilliams: Department of Interventional Radiology, University of California, Los Angeles, 757 Westwood Plaza, Suite
2125C, Los Angeles, CA 90095.
Dr. Meek: Department of Interventional Radiology, Universityof Arkansas for Medical Sciences, 4301 West Markham Street,
Slot 556, Little Rock, AR 72205.
Dr. Mei-Zahav: Pulmonary Institute, Schneider CMCI, 14 Kaplan Street, Petach Tikva, 49202, Israel.
Dr. Piccirillo: Department of Otolaryngology-Head & Neck
Surgery, Washington University School of Medicine, 660
South Euclid Avenue, Campus Box 8115, St. Louis, MO 63110.
Dr. Porteous: Department of Genetics University of Edinburgh, Center of Molecular Medicine, Crewe Road, Edinburgh EH4 2XU, Scotland.
Dr. Radovanovic: Department of Neurosurgery, University
Health Network, Toronto Western Hospital, 399 Bathurst
Street, Toronto, ON M5T 2S8, Canada.
Dr. Rochon: University of Colorado Hospital, 12631 East 17th
Avenue, Mailstop 8200, Aurora, CO 80048.
Dr. Rodriguez-Lopez: Department of Pulmonology, Massachusetts General Hospital, 55 Fruit Street, Bulﬁnch 148, Boston, MA 02114.
Dr. Sabba: Department of Internal Medicine, University ofBari, Policlinico, Piazza Giulio Cesare, Bari, 70124 Italy.
Dr. Serra: Department of Internal Medicine, Hospital Italiano
de Buenos Aires, Araoz 2067, Buenos Aires 1425, Argentina.
Dr. Shovlin: Department of Pulmonology, Hammersmith Hospital, Du Cane Road, London W12 0NN, England.
Dr. White: Division of Pediatric Immunology and Rheumatology, Washington University School of Medicine, One Children's Place, St. Louis, MO 63110.
Dr. Winship: Genomic Medicine, Royal Melbourne Hospitaland University of Melbourne, Grattan Street, Melbourne, VIC
3002, Australia.
Dr. Zarrabeitia: Hospital Sierrallana, Barrio Ganzo s/n, 39300
Torrelavega, Cantabria, Spain.
Author Contributions: Conception and design: M.E. Faugh-nan, J.J. Mager, S.W. Hetts, V.A. Palda, E. Buscarini, E. Deslandres, R.S. Kasthuri, F. Ratjen, M.S. Chesnutt, E. de Gussem, A.
Hammill, A.D. Kjeldsen, J. McDonald, M. Mei-Zahav, S. Olitsky,
B. Plahn, M.C. Post, C. Shovlin, A.J. White, I. Winship.
Analysis and interpretation of the data: M.E. Faughnan, J.J.
Mager, S.W. Hetts, V.A. Palda, E. Buscarini, E. Deslandres, R.S.
Kasthuri, D. Poetker, F. Ratjen, M.S. Chesnutt, M. Clancy, K.J.
Annals of Internal Medicine

Whitehead, H. Al-Samkari, M. Conrad, C. Crocione, J. Darling,
E. de Gussem, P. Foy, U. Geisthoff, J.R. Gossage, K. Heimdal,
K. Henderson, V.N. Iyer, A.D. Kjeldsen, M. Komiyama, J. McDonald, J. McMahon, J. McWilliams, M.E. Meek, M. MeiZahav, S. Olitsky, S. Palmer, R. Pantalone, J.F. Piccirillo, M.E.M.
Porteous, I. Radovanovic, P.J. Rochon, C. Sabba, M. Serra, C.
Shovlin, D. Sprecher, A.J. White, I. Winship, R. Zarrabeitia.
Drafting of the article: M.E. Faughnan, J.J. Mager, S.W. Hetts,
V.A. Palda, K. Lang-Robertson, E. Buscarini, E. Deslandres, R.S.
Kasthuri, A. Lausman, D. Poetker, F. Ratjen, M.S. Chesnutt, M.
Clancy, K.J. Whitehead, M. Chakinala, E. de Gussem, J.R. Gossage, K. Henderson, V.N. Iyer, M. Mei-Zahav, R. Pantalone, B.
Plahn, M.C. Post, P.J. Rochon, M. Serra, R. Zarrabeitia.
Critical revision of the article for important intellectual content: M.E. Faughnan, J.J. Mager, S.W. Hetts, V.A. Palda, E.
Buscarini, E. Deslandres, R.S. Kasthuri, A. Lausman, D. Poetker,
F. Ratjen, M.S. Chesnutt, K.J. Whitehead, H. Al-Samkari, M. Chakinala, M. Conrad, J. Darling, E. de Gussem, S. Dupuis-Girod, P.
Foy, U. Geisthoff, J.R. Gossage, A. Hammill, K. Heimdal, K. Henderson, V.N. Iyer, A.D. Kjeldsen, K. Korenblatt, J. McWilliams, M.
Mei-Zahav, R. Pantalone, J.F. Piccirillo, M.E.M. Porteous, M.C.
Post, I. Radovanovic, P.J. Rochon, J. Rodriguez-Lopez, C. Sabba,
M. Serra, C. Shovlin, D. Sprecher, A.J. White, I. Winship, R.
Zarrabeitia.
Final approval of the article: M.E. Faughnan, J.J. Mager, S.W.
Hetts, V.A. Palda, K. Lang-Robertson, E. Buscarini, E. Deslan-

Annals of Internal Medicine

dres, R.S. Kasthuri, A. Lausman, D. Poetker, F. Ratjen, M.S.
Chesnutt, M. Clancy, K.J. Whitehead, H. Al-Samkari, M. Chakinala, M. Conrad, D. Cortes, C. Crocione, J. Darling, E. deGussem, C. Derksen, S. Dupuis-Girod, P. Foy, U. Geisthoff, J.R.
Gossage, A. Hammill, K. Heimdal, K. Henderson, V.N. Iyer,
A.D. Kjeldsen, M. Komiyama, K. Korenblatt, J. McDonald, J.
McMahon, J. McWilliams, M.E. Meek, M. Mei-Zahav, S. Olitsky,
S. Palmer, R. Pantalone, J.F. Piccirillo, B. Plahn, M.E.M. Porteous, M.C. Post, I. Radovanovic, P.J. Rochon, J. RodriguezLopez, C. Sabba, M. Serra, C. Shovlin, D. Sprecher, A.J. White,
I. Winship, R. Zarrabeitia.
Provision of study materials or patients: F. Ratjen, E. de Gussem, J. McDonald.
Obtaining of funding: M.E. Faughnan, M. Clancy, J. McMahon,
I. Winship.
Administrative, technical, or logistic support: M.E. Faughnan,
S.W. Hetts, V.A. Palda, C. Derksen, S. Olitsky, B. Plahn.
Collection and assembly of data: M.E. Faughnan, J.J. Mager,
S.W. Hetts, K. Lang-Robertson, E. Buscarini, E. Deslandres,
R.S. Kasthuri, A. Lausman, D. Poetker, F. Ratjen, H. Al-Samkari,
M. Chakinala, D. Cortes, E. de Gussem, J.R. Gossage, A. Hammill, K. Henderson, V.N. Iyer, A.D. Kjeldsen, M. Komiyama, J.
McDonald, J. McWilliams, M. Mei-Zahav, M.C. Post, I. Radovanovic, P.J. Rochon, J. Rodriguez-Lopez, M. Serra, C. Shovlin,
A.J. White, I. Winship, R. Zarrabeitia.

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