Journal of Adolescent Health 71 (2022) 127e131

www.jahonline.org

Adolescent health brief

Management of Contraception in Adolescent Females With

Hormone-Related Venous Thromboembolism
Kristin N. Maher, M.D., Ph.D. a, *, Elisabeth H. Quint, M.D. b, and Angela C. Weyand, M.D. a
a
Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan
b
Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan

Article history: Received October 5, 2021; Accepted February 19, 2022

Keywords: Adolescent. venous thromboembolism; Deep vein thrombosis; Pulmonary embolism; Contraception; Adolescent pregnancy

A B S T R A C T
IMPLICATIONS AND
CONTRIBUTION
Purpose: Management of contraception in adolescent females with hormone-related venous
thromboembolism (VTE) is challenging. We examined the characteristics of this patient population
Adolescent females with
and outcomes, including recurrent VTE, heavy menstrual bleeding, and pregnancy. deep vein thrombosis or
Methods: We performed a single-institution retrospective cohort study of adolescents with a new pulmonary embolism are
diagnosis of VTE and concurrent use of estrogen- and/or progestin-containing medication (N ¼ 89). often advised to stop hor-
We collected data on additional risk factors for thrombosis, management of hormone therapy, and mone therapy to reduce
anticoagulation. We compared outcomes between patients with prescribed contraception within the risk for recurrent
the year after their VTE diagnosis (n ¼ 52) with those without (n ¼ 37). thrombosis. Early involve-
Results: At least one additional risk factor for thrombosis was identified in 92% of patients, and 73% ment of reproductive
had two or more. The most common additional thrombosis risk factors were obesity (35%), family health care providers,
history (33%), and recent immobility (33%). Ninety-seven percent of patients were receiving contraceptive counseling,
combined hormonal medications, and 42% of patients had their medication stopped and not and access to contracep-
replaced with an alternative. Heavy menstrual bleeding was reported while on anticoagulation in tion associated with low
46% of patients with a documented menstrual history. Recurrent VTE occurred in 9.0% of patients. thrombosis risk are
The group without prescribed contraception had a significantly higher rate of pregnancy in the two needed to prevent preg-
years after VTE diagnosis (18% vs. 1.9%, p ¼ .04). Two pregnancies occurred while on warfarin. nancy and anticoagulant-
Discussion: Early assessment of contraceptive needs and menstrual bleeding symptoms are associated heavy men-
needed after diagnosis of hormone-related VTE in adolescent females. Access to contraceptive strual bleeding.
methods associated with low thrombosis risk is important for the prevention of unplanned
pregnancy in this patient population.
Ó 2022 Society for Adolescent Health and Medicine. All rights reserved.

The incidence of venous thromboembolism (VTE) in female
adolescents is 1.1e3 per 10,000 per year [1,2]. Many risk factors
for VTE in this population are common along the pediatric age
spectrum, including immobility, infection, presence of a central
Conflicts of interest: No authors have any conflicts of interest to disclose.
* Address correspondence to: Kristin N. Maher, M.D., Ph.D., Division of Pedi-
atric Hematology/Oncology, Seattle Children’s Hospital, 4800 Sand Point Way
NE, MB.8.501, Seattle, WA 98105.
E-mail address: kristin.maher@seattlechildrens.org (K.N. Maher).
venous catheter, and acquired or hereditary thrombophilia. The
risk factors for VTE found more uniquely in the adolescent
population include obesity, tobacco use, pregnancy, and exoge-
nous hormone use. Hormone use is rarely the only risk factor in
adolescent patients with VTE, with 96% of patients found to have
at least one additional risk factor, and obesity found to be a
concomitant risk factor in as many as 50% [2e4].
Combined oral contraceptives (COCs) containing ethinyl
estradiol and progesterone are associated with a three- to six-

1054-139X/Ó 2022 Society for Adolescent Health and Medicine. All rights reserved.
https://doi.org/10.1016/j.jadohealth.2022.02.009
128 K.N. Maher et al. / Journal of Adolescent Health 71 (2022) 127e131
fold increase in risk for VTE [5,6], and the risk may be even higher
with nonoral combined hormonal contraceptives, such as the
patch and vaginal ring [7]. There are limited data showing a two-
to three-fold increase in risk with the injectable progestin depot
medroxyprogesterone (DMPA) [8], and there may be some
increased risk with high doses of the oral progestin norethin-
drone because of in vivo conversion to ethinyl estradiol [9].
When describing the risk associated with contraceptive
methods, it is also important to consider the risk associated with
pregnancy. The risk for VTE may be increased as much as 10-fold
in adolescent pregnancy [1], higher in comparison to any con-
traceptive method. The Centers for Disease Control and Preven-
tion Medical Eligibility Criteria for Contraceptive Use
recommends against the use of estrogen in patients with a his-
tory of VTE, giving combined hormonal contraception a category
3 or 4 designation depending on VTE recurrence risk [10]. The
use of DMPA, levonorgestrel-releasing intrauterine devices
(IUDs), progestin-only pills (POPs), and progestin-only implants
in patients with history of VTE are all assigned to category 2, with
advantages considered to outweigh the risks.
Adolescent females diagnosed with VTE are often advised to
stop their hormone therapy immediately out of concern for
recurrence. Providing counseling and access to alternatives is
challenging in the acute setting. Regardless of the initial indica-
tion for hormone therapy, abrupt discontinuation puts patients
with hormone-related VTE at risk for unintended pregnancy.
Unintended pregnancy is particularly problematic in the subset
of patients receiving warfarin for therapeutic anticoagulation
because of the strong association between maternal warfarin use
in the first trimester and fetal adverse effects [11]. Abrupt
discontinuation also puts patients at risk for anticoagulant-
associated heavy menstrual bleeding, a complication that is
underrecognized and undertreated in women undergoing
treatment for VTE [12]. This study was designed to examine the
characteristics of the adolescent patient population with
hormone-related VTE and the effects of contraceptive manage-
ment on recurrent VTE, heavy menstrual bleeding, and
pregnancy.
Methods
We performed a single-institution retrospective cohort study
of patients aged 13e20 years seen between 2010 and 2020 with a
new diagnosis of deep vein thrombosis and/or pulmonary
embolism and concurrent use of estrogen- and/or progestin-
containing medication. Patients were identified in the
electronic medical record using DataDirect (https://datadirect.
med.umich.edu/), a self-service tool enabling access to di-
agnoses, encounters, procedures, laboratories, and medications
for more than four million unique patients across the University
of Michigan Health System. Patients were identified using age at
encounter and International Classification of Diseases, Ninth
Revision, or International Classification of Diseases, Tenth Revi-
sion, codes. We did not use recorded medication lists to identify
patients in DataDirect because in many cases, oral contraceptives
were stopped on admission and never entered as a medication
into the patient’s chart. We used manual chart review to deter-
mine hormone use at VTE diagnosis.
We excluded patients if they had a stroke, arterial thrombosis,
superficial vein thrombosis, were receiving only physiologic
hormone replacement, were pregnant at diagnosis, or were lost
to follow-up. We extracted demographic information, medical
and family history, thrombophilia testing results, VTE treatment,
and VTE recurrences. We defined family history as significant if a
first- or second-degree relative had unprovoked thrombosis
under the age of 50 years. We calculated the number of throm-
bosis risk factors for each patient, including those categorized by
the International Society on Thrombosis and Haemostasis [13,14],
the classic hereditary thrombophilias [15], and abnormalities of
venous anatomy such as May-Thurner and thoracic outlet syn-
dromes [16,17]. We considered a patient to have received an in-
definite course of anticoagulation if the patient remained on
anticoagulation at the last charted encounter and notes indicated
a plan to continue indefinitely. We extracted information about
management of hormone therapy in the year after VTE diagnosis,
menstrual bleeding symptoms, and pregnancies. In many cases,
IUDs were not placed at our institution, and it was not possible to
determine from chart review the type of IUD used, and so, this
information was not collected. We considered patients to have
heavy menstrual bleeding if chart notes indicated there was an
impact on quality of life at any time after VTE diagnosis, aligning
with the American College of Gynecology accepted definition
[18]. No standardized methods were used to measure quality of
life. We did not collect information about the management of
anticoagulation or VTE recurrences during or after pregnancy.
We divided patients into two cohorts, those who were on
some form of prescribed contraception by 1 year after their VTE
diagnosis and those who were not. We compared baseline
characteristics between the cohorts, including demographic in-
formation, number of other thrombosis risk factors, proportion
of patients with a thrombophilia diagnosis, hormone therapy
duration and type, and VTE therapy duration and type. We then
compared three outcomes between the cohorts: VTE recurrence,
heavy menstrual bleeding, and pregnancy within 2 years of VTE
diagnosis. Given our small sample sizes, we determined p values
using the Fisher exact test for proportions and the Mann-
Whitney U test for medians. Statistical significance was met if p
 .05. This study was approved by the Institutional Review Board
of the University of Michigan.
Results
A total of 89 patients met the inclusion criteria. The median
age at VTE diagnosis was 18.1 years, with a range of 13.6e
20.0 years. The median body mass index was 26.5 kg/m2. At least
one additional risk factor for thrombosis was identified in 92% of
patients, and 73% had two or more (Figure 1). The most common
risk factors were obesity (35%), significant family history (33%),
and immobility or surgery with the previous 2 weeks (33%).
None of the patients had a pre-existing thrombophilia diagnosis.
Testing for thrombophilia was performed after VTE in 72% of
patients, and 34% of those had a positive finding. The most
common findings were heterozygous Factor V Leiden (15% of all
patients), antiphospholipid antibodies (5.6% of all patients), and
prothrombin gene mutation (2.2% of all patients). There were
four additional patients with positive findings, including one
patient with each of the following: homozygous Factor V Leiden,
protein C deficiency, protein S deficiency, and antithrombin III
deficiency. The median duration of hormone therapy at VTE
diagnosis was 5.5 months. Eighty-six (97%) patients were
receiving estrogen-containing medication; this was a pill in 90%,
vaginal ring in 5.6%, and contraceptive patch in 1.1%. The specific
medication name and dose were identifiable from the chart in
73% of patients on a COC. Of those, the median daily ethinyl
 K.N. Maher et al. / Journal of Adolescent Health 71 (2022) 127e131
Figure 1. Additional risk factors for thrombosis in adolescent females with hormone-related venous thromboembolism (N ¼ 89).
estradiol dose was 30 mcg, and the progestin component was a
first- or second-generation progestin in 36%, third-generation
progestin in 43%, and fourth-generation progestin (drospir-
enone) in 21%. Three (3.4%) patients were using a progestin-only
medication, including POP, DMPA, and subcutaneous implant. All
three of these patients had three additional risk factors for
thrombosis, including all three having a central venous catheter
in place.
Seventy-six (85%) patients received a finite course of anti-
coagulation, with a median duration of 3 months. Eleven patients
received indefinite anticoagulation. The most common reason
given for indefinite anticoagulation was antiphospholipid syn-
drome, diagnosed in five patients. Anticoagulants prescribed at
discharge included low molecular weight heparin in 47% of all
patients, warfarin in 25%, apixaban in 14%, and rivaroxaban in
12%. Forty percent of patients switched anticoagulant at least
once. Two patients received no anticoagulation, one due to
increased bleeding risk and one because the thrombus was small
and incidentally found. Twenty-five (28%) patients received
thrombolysis in addition to anticoagulation.
All progestin-only therapies were continued without inter-
ruption. Four patients continued estrogen-containing COCs; this
was in the setting of indefinite anticoagulation in three patients.
Of the 45 patients prescribed replacement for estrogen-
containing methods in the year after VTE diagnosis, 42% had an
IUD, 40% were prescribed a POP, 11% received DMPA, and 6.2%
had a progestin implant.
Eight patients had a VTE recurrence, with an overall rate of
9.0%. All recurrences were within 2 years of initial VTE diagnosis.
One patient with recurrence had a progestin implant, one was
taking a POP, one had an IUD, and the remaining five were
receiving no hormone therapy. Patients with a recurrence had,
on average, two nonhormone risk factors for thrombosis. Half of
the recurrences were in patients with BMI >30 kg/m2, one
recurrence happened during an anticoagulation hold around the
time of surgery, and one occurred in a patient found to have
homozygous Factor V Leiden mutation. No patients were
receiving anticoagulation or any estrogen at the time of recur-
rence. Discussion of heavy menstrual bleeding was documented
at follow-up for 51% of patients, with heavy menstrual bleeding
reported in 46% of those. Seven (7.9%) patients were pregnant
129
within 2 years. The median age at pregnancy was 18.4 years, with
a range of 15.8e19.0 years. Only one of these patients was pre-
scribed contraception in the year after her VTE diagnosis. Two of
the pregnancies occurred while on warfarin.
We compared outcomes between patients with some form of
prescribed contraception within a year of their VTE diagnosis to
those without (Table 1). There was no significant difference in
the baseline characteristics between the groups. There was no
significant difference between the groups in proportion of pa-
tients with recurrent thrombosis or heavy menstrual bleeding.
The group without prescribed contraception did have a signifi-
cantly higher rate of pregnancy in the 2 years after VTE diagnosis
(18% vs. 1.9%, p ¼ .04).
Discussion
Most patients included in this study had multiple risk factors
for thrombosis, consistent with previous reports. Combined
hormonal contraception was being used in most of the patients,
with variation in the type of progestin and the dose of ethinyl
estradiol. The few patients receiving a progestin only also had a
central venous catheter, a very strong risk factor for thrombosis
[19], suggesting that the progestin represented minimal relative
contribution to their risk. Prevention of recurrent thrombosis in
patients with a history of hormone-related VTE often requires
more than modifying hormone therapy and may involve man-
aging chronic medical conditions and addressing modifiable risk
factors such as obesity.
The low VTE recurrence rate in the patients who received
prescribed contraception in the year after their VTE diagnosis is
reassuring and unsurprising because the majority used
progestin-only methods. A small minority of patients had COCs
continued in the setting of ongoing therapeutic anticoagulation.
Although this approach does not align with the Centers for
Disease Control and Prevention Medical Eligibility Criteria for
Contraceptive Use recommendations, it is sometimes considered
if alternatives are not acceptable to the patient for contraceptive
purposes. Studies in adult women show no increased recurrence
risk with COC use in those who remain on concurrent anti-
coagulation [20], and adult women have a higher baseline
130 K.N. Maher et al. / Journal of Adolescent Health 71 (2022) 127e131

Table 1
Patient characteristics, treatment characteristics, and outcomes for adolescents with hormone-related VTE, grouped by management of contraception in the year after
VTE diagnosis

Management of contraception p valuea

Stopped and not replaced (n ¼ 37) Replaced or continued (n ¼ 52)

Patient characteristics
Median age (IQR) 17.7 (16.9e19.0) 18.4 (17.0e19.9) .18
Race (%) White 33 (89) 46 (88) >.99
Black/African American 2 (5.4) 5 (9.6) .69
Asian 2 (5.4) 1 (1.9) .57
Ethnicity (%) Hispanic 1 (2.7) 0 (0) .42
Median BMI (IQR) 26 (22e36) 27 (22e39) .67
Number of thrombosis risk factors (%) 1 (hormone only) 3 (8.1) 4 (7.7) >.99
2 10 (27) 11 (21) .61
3 24 (65) 37 (71) .64
Thrombophilia diagnosis (%) 11 (30) 11 (21) .46

Hormone characteristics

Type of hormone therapy (%) Estrogen containing 37 (100) 49 (94)b .26

Median duration in months (IQR)c 3.0 (2.0e12.0)x 7.0 (3.0e24.0)xx .09

VTE treatment characteristics

Anticoagulation (%) None 1 (2.7) 1 (1.9) >.99

Finite course 31 (83.8) 45 (86.5) .77
Indefinite 5 (13.5) 6 (11.5) >.99
Thrombolysis (%) 11 (30) 14 (27) .81

Outcomes

Heavy menstrual bleeding (%d) 7 (47)y 14 (45)yy >.99

Recurrence (%) 5 (14) 3 (5.8) .27
Pregnancy within 2 years (%) 6 (18) 1 (1.9) .04

BMI ¼ body mass index; IQR ¼ interquartile range; VTE ¼ venous thromboembolism.
a
Calculated using Fisher exact test or Mann-Whitney U test.
b
Replaced with progestin-only pill, depot medroxyprogesterone, or intrauterine device in 45 (92%) of these cases.
c
For patients with documentation of hormone therapy duration (xn ¼ 27,xxn ¼ 35).
d
Percent of patients with documented discussion about menstrual bleeding at follow-up (yn ¼ 15,yyn ¼ 31).

thrombosis risk than adolescents. Further studies are needed to
determine the risk of this approach in adolescents.
There was a significant rate of heavy menstrual bleeding in
our patient population regardless of how hormone therapy was
managed, although documentation was limited. Obtaining and
documenting a complete menstrual history is particularly
important in adolescents on anticoagulation because many may
not know what constitutes a “normal” period. In addition,
because of stigma surrounding menstruation, patients may not
seek care for it without proactive support from medical pro-
viders. Prescribers of anticoagulation need to improve on taking
an adequate menstrual history and assessing for sequalae of
heavy menstrual bleeding, such as iron deficiency.
The significantly higher rate of pregnancy in those patients for
whom combined hormone medications were stopped and not
replaced raises the question of whether these patients had sufficient
counseling about low-risk contraceptive methods and whether
they had access to these alternatives. With the limitations of our
study, we could not confirm that pregnancies were unplanned, but
this is a concern, particularly because two of the pregnancies
occurred while on warfarin, a pregnancy category X medication.
The main strength of our study is that data regarding con-
traceptive use were manually collected from charts by medical
providers. This method allowed us to collect more accurate in-
formation about a larger cohort of patients than would have been
identified using electronic extraction alone because medications
and devices used for contraception are often not documented on
medication lists or in any other systematic way. Overall, our
study is limited by small sample size and variation in quality of
chart documentation. All patients received care in our system
from a pediatric or adult hematologist, but some received
reproductive health care outside of our health system, and there
was more limited documentation of these encounters. Further
investigation with multicenter studies is needed to determine
effective strategies for the management of contraception and
heavy menstrual bleeding in adolescents with VTE.
In addition to follow-up with a hematologist to assess their
ongoing thrombosis risk, adolescents with hormone-related VTE
benefit from early assessment of reproductive health care needs.
Early involvement of reproductive health care providers, con-
traceptive counseling, and access to contraception associated
with low thrombosis risk are needed to prevent pregnancy and
anticoagulant-associated heavy menstrual bleeding. High prior-
ity should be placed on access to contraceptive methods asso-
ciated with lower risk for thrombosis, such as IUDs, low-dose
POPs, progestin implants, and DMPA. When making recom-
mendations for modification or discontinuation of hormone
therapy, providers must also carefully consider the risks of
pregnancy and ensure patients have the information they need
to make reproductive decisions with these risks in mind.
Acknowledgments
Apart from the previously mentioned authorship contribu-
tions, there were no substantive contributions from others to this
work. An incomplete version of this work was presented as an
 K.N. Maher et al. / Journal of Adolescent Health 71 (2022) 127e131
oral presentation at the American Society of Pediatric Hematol-
ogy and Oncology Conference in 2021 (reference: Maher KN,
Quint E, Weyand AC: Hormone-Related Thrombosis in Adoles-
cent Girls: Risk Factors and Management Challenges, Oral Pre-
sentation, American Society of Pediatric Hematology and
Oncology Conference, Portland, OR, April 2021.).
Authors’ Contribution: K.N.M. designed and conceptualized
the study, designed the data collection instruments, collected
data, carried out the initial analysis, drafted the initial article, and
reviewed and revised the article. A.C.W. conceptualized and
designed the study, designed the data collection instruments,
supervised data collection and analysis, and critically reviewed
the article for important intellectual content. E.HQ. conceptual-
ized and designed the study, supervised data collection and
analysis, and critically reviewed the article for important intel-
lectual content. All authors approved the final article as sub-
mitted and agree to be accountable for all aspects of the work.
Funding Sources
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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