Original Research
Association of Progestogens and Venous
Thromboembolism Among Women of
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Reproductive Age
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Richard H. Cockrum, MD, Jackie Soo, ScD, Sandra A. Ham,
and Shari G. Snow, MD
OBJECTIVE: To evaluate associations between use of
seven progestogens and incident acute venous throm-
boembolism (VTE) among women of reproductive age.
METHODS: This nested matched case–control study
identified women aged 15–49 years from January 1, 2010,
through October 8, 2018, in the IBM MarketScan data-
bases, a nationwide sample of private insurance claims in
the United States. After exclusions, 21,405 women with
incident acute VTE (case group), identified by diagnosis
codes, were matched 1:5 by year of birth and index date
From the Department of Obstetrics and Gynecology and the Department of
Medicine, University of Chicago Medicine, the Center for Health and Social
Sciences, University of Chicago, Chicago, and the Department of Obstetrics and
Gynecology, NorthShore University HealthSystem, Evanston, Illinois; and
Sandra Ham Consulting, Buffalo, New York.
Presented at the International Federation of Gynecology and Obstetrics’ 23rd
World Congress of Gynecology and Obstetrics, held virtually, October 21–28,
2021; and at the AAGL 50th Global Congress on MIGS, November 14–17,
2021, Austin, Texas.
This project was supported by the National Center for Advancing Translational
Sciences of the National Institutes of Health through Grant Number
5UL1TR002389-02 that funds the Institute for Translational Medicine. The
content is solely the responsibility of the authors and does not necessarily represent
the official views of the NIH.
Source data and raw data of the sample used in this study are not publicly
available in accordance with data-sharing limits by IBM MarketScan Research
Databases but may be accessed under licensure with the company.
Each author has confirmed compliance with the journal’s requirements for
authorship.
Corresponding author: Shari G Snow, MD, Department of Obstetrics and
Gynecology, University of Chicago Medicine Chicago, IL; email: ssnow@
bsd.uchicago.edu.
Financial Disclosure
Kenneth S. Cohen received travel reimbursement from the Japan Cancer Society
for an awards ceremony in 2019. He received payment from the American
Medical Forum for independent CME talks in 2019, and honoraria for
streaming lectures in 2020. He also received honoraria from Bioascend for a
lecture at the International Ultmann Chicago Lymphoma Symposium 2022. The
other authors did not report any potential conflicts of interest.
© 2022 by the American College of Obstetricians and Gynecologists. Published
by Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0029-7844/22
VOL. 140, NO. 3, SEPTEMBER 2022
© 2022 by the American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
MS, Kenneth S. Cohen, MD,
through risk set sampling to 107,025 women without prior
VTE (control group). From lowest to highest systemic dose
based on a modified hierarchy, progestogens studied were
levonorgestrel-releasing intrauterine device (LNG-IUD),
oral norethindrone, etonogestrel implant, oral progester-
one, oral medroxyprogesterone acetate, oral norethin-
drone acetate, and depot medroxyprogesterone acetate
(DMPA). Conditional logistic regression models adjusted
for 16 VTE risk factors were used to estimate odds ratios
and 99% CIs for incident acute VTE associated with cur-
rent progestogen use compared with nonuse. The primary
analysis treated each progestogen as a binary exposure.
Dose, which varied for oral formulations, and chronicity
were explored separately. Significance was set at P ,.01 to
allow for multiple comparisons.
RESULTS: Current use of higher-dose progestogens was
significantly associated with increased odds of VTE com-
pared with nonuse (oral norethindrone acetate: adjusted
odds ratio [aOR] 3.00, 99% CI 1.96–4.59; DMPA: aOR 2.37,
99% CI 1.95–2.88; and oral medroxyprogesterone acetate:
aOR 1.98, 99% CI 1.41–2.80). Current use of other proges-
togens was not significantly different from nonuse (LNG-
IUD, etonogestrel implant, and oral progesterone) or had
reduced odds of VTE (oral norethindrone). Sensitivity
analyses that assessed misclassification bias supported
the primary findings.
CONCLUSION: Among reproductive-aged women using
one of seven progestogens, only use of norethindrone
acetate and medroxyprogesterone acetate—considered
higher-dose progestogens—was significantly associated with
increased odds of incident acute VTE. The roles of progesto-
gen type, dose, and indication for use warrant further study.
(Obstet Gynecol 2022;140:477–87)
DOI: 10.1097/AOG.0000000000004896
V
enous thromboembolism (VTE), defined as deep
venous thrombosis, pulmonary embolism, or
both, is associated with severe morbidity and mortal-
ity and is increasing in the United States.1 For women
OBSTETRICS & GYNECOLOGY 477
 with significant VTE risk factors, in which estrogen
use is contraindicated, progestogen-only medications
(progestogens) have been recommended as alternative
forms of contraception and treatments for benign
menstrual disorders.2,3 However, the assumption that
progestogens are safer may not hold for all types and
doses.
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Twenty-two studies have assessed the association
between progestogen use and VTE, but most were
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judged to be of poor-to-fair quality and limited by small
sample sizes.4–12 In their systematic review, Tepper et al
described a potential dose–response relationship based
on a hierarchy by Bergendal et al that reflected systemic
effects (eg, ovulation inhibition).4,13 The available evi-
dence suggests that use of the very-low-dose levonorges-
trel-releasing intrauterine device (LNG-IUD), low-dose
oral norethindrone, or the moderate-dose etonogestrel
subcutaneous contraceptive implant does not increase
VTE risk. However, a recent meta-analysis found that
use of the high-dose injectable contraceptive depot me-
droxyprogesterone acetate (DMPA) was associated with
a 2.6-fold increase in odds of VTE.7,12,14,15 Noncontra-
ceptive progestogens (eg, oral norethindrone acetate, oral
medroxyprogesterone acetate, and oral progesterone),
have also been associated with a 2.4- to 5.9-fold increase
in odds of VTE in four small studies.10,16–18
In contrast to clinical guidelines that have ques-
tioned studies on DMPA use, some authors have
urged caution when prescribing higher-dose proges-
togens to individuals at increased VTE risk.2,4,10,16,19–
25 This nested matched case–control study aimed to
evaluate associations between current use of seven
progestogens and incident acute VTE, compared with
nonuse of any progestogen.
METHODS
The IBMÒ MarketScanÒ Commercial Claims and
Encounters Databases contain routinely collected,
de-identified data for individuals and their dependents
with employer-based insurance and some nongroup
commercial health plans in the United States.26 Data-
bases include enrollment records, inpatient and out-
patient adjudicated medical claims, and pharmacy
claims for filled prescriptions.
Case-defining VTE diagnoses (DVT, PE, or both)
were identified by International Classification of
Diseases, Ninth Revision (ICD-9) or International
Classification of Diseases, Tenth Revision (ICD-10)
diagnosis codes from inpatient and outpatient claims
(Appendix 1, available online at http://links.lww.
com/AOG/C813). The case group included women
of reproductive age, defined as age 15–49 years, who
were newly diagnosed with VTE from January 1,
478 Cockrum et al Progestogens and Venous Thromboembolism
© 2022 by the American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
2010 (when diagnosis codes first differentiated acute
and chronic VTE), through October 8, 2018 (the most
recently available data).9,11,27,28 The index date for
women in the case group was defined as the inpatient
date of admission or outpatient date of service. Inpa-
tient diagnoses adjudicated at the time of discharge
have been shown to be more accurate than outpatient
diagnoses.29 Outpatient diagnoses required corrobo-
ration with a new anticoagulation prescription within
42 days before or after the index date.7,30,31 Finally,
continuous enrollment in medical and pharmacy ben-
efit coverage was required from 1 year before the
index date through 84 days after the index date, to
ascertain conditions for exclusion.
Exclusions were applied to create a sample
representative of women in the case group with
incident acute VTE who could have been exposed
to progestogens at typical doses for contraception
or treatment of benign menstrual disorders (eg,
endometriosis, abnormal uterine bleeding). We
excluded women with nonqualifying VTE diagno-
ses (eg, chronic, pregnancy-related) or with any
earlier anticoagulation prescription that could indi-
cate recurrent VTE. Superficial venous thrombosis
was evaluated as a covariate rather than an exclu-
sion criterion.2,19 We then excluded women diag-
nosed with conditions that can be treated with ultra-
high-dose progestogens (eg, breast cancer, ductal
carcinoma in situ, endometrial cancer, endometrial
intraepithelial neoplasia or hyperplasia, and
cachexia or acquired immune deficiency syn-
drome) or who had a megestrol acetate prescription
within 1 year before the index date. Prior studies
have already demonstrated increased odds of VTE
and mortality in these settings.16,32,33 Women in
the case group who were determined to be pregnant
or postpartum based on claims within 42–84 days
before or after the index date were then excluded to
allow for an adequate washout period and for new
progestogen exposure (Appendix 1, http://links.
lww.com/AOG/C813). Similarly, we excluded
women in the case group with exposure to a med-
ication containing estrogen within 84 days before
the index date.
Women in the control group were initially
individually matched 50:1 to women in the case
group by risk set sampling, with replacement based
on year of birth and index date. The index date for
women in the control group was set to the index date
of the matched women in the case group so that the
surveillance periods overlapped exactly within each
stratum. Additional confounders were incorporated as
covariates instead of matching criteria as
OBSTETRICS & GYNECOLOGY
 recommended by STROBE (Strengthening the Re-
porting of Observational Studies in Epidemiology)
guidelines.34 Propensity score matching may have
reduced bias from differences in measurable VTE risk
factors between women in the case group and women
in the control group. However, it would have pre-
vented use of a single study population for multiple
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progestogen exposures and reduced statistical effi-
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Women in the control group could not have any
VTE diagnosis or anticoagulation prescriptions in
the available records before the index date. This initial
larger pool ensured that an adequate number of eligi-
ble women remained for the control group after
exclusions that were time dependent. After applying
enrollment and exclusion criteria, excess women in
the control group for each woman in the case group
were randomly removed to reach a 5:1 ratio. Women
in the case group with inadequate matched women in
the control group were excluded from the sample.
Exposures to four oral progestogens (oral noreth-
indrone, oral progesterone, oral medroxyprogester-
one acetate, and oral norethindrone acetate) were
identified by filled outpatient prescriptions as proxies
for actual use as prescribed. Exposures to three
nonoral progestogens (LNG-IUD, etonogestrel
implant, and DMPA) were identified by pharmacy
and medical claims (Appendix 1, http://links.lww.
com/AOG/C813). Claims data did not allow for
direct ascertainment of indication for progestogen
use or for identification of all contraindications for
alternatives. Some progestogens were more likely
used for contraception only (oral norethindrone and
etonogestrel implant), treatment only (oral progester-
one, oral medroxyprogesterone acetate, and oral nor-
ethindrone acetate), or both (LNG-IUD and DMPA).
Definitions of exposure characteristics (Table 1) were
generated for additional analyses of recency, dose,
and chronicity. Categories reflected common pre-
scribing practices, assumed that progestogen use near-
est the index date was most important, and aligned
with prior studies.14,28,30,35 Users with more than one
current or recent progestogen exposure were classi-
fied as having mixed use. The primary progestogen
for analysis was selected as that with the highest sys-
temic dose using a dose hierarchy by Bergendal et al
modified to incorporate noncontraceptive progesto-
gens (from lowest to highest: LNG-IUD, oral noreth-
indrone, etonogestrel implant, oral progesterone, oral
medroxyprogesterone acetate, oral norethindrone
acetate, DMPA).13,36,37 The hierarchy did not account
for potential pharmacologic differences in oral and
nonoral administration or for dosing patterns (eg,
VOL. 140, NO. 3, SEPTEMBER 2022 Cockrum et al
© 2022 by the American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
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cyclic, continuous). Current and recent users of more
than two progestogens were excluded from analyses
as outliers.
Covariates were identified using diagnosis and
procedure codes from inpatient and outpatient claims
during the 1 year before the index date (Appendix 1,
http://links.lww.com/AOG/C813). We included 16
VTE risk factors as prespecified confounders based
on prior literature: obesity (body mass index [BMI,
calculated as weight in kilograms divided by height in
meters squared] 30 or higher), history of smoking, ath-
erosclerotic cardiovascular disease, hypertension, con-
gestive heart failure, chronic kidney disease,
rheumatoid arthritis, systemic lupus erythematous,
inflammatory bowel disease, cancer (excluding nonme-
lanoma skin cancer and breast and uterine cancers
based on study exclusion criteria), hemiplegia or para-
plegia, hypercoagulable state, superficial venous throm-
bosis, varicose veins, history of surgery or lower
extremity fracture within 180 days before the index
date, and history of hospitalization within 180 days
before the index date.1–3,9,11,27,38
Descriptive statistics were calculated for charac-
teristics of women in the case and control groups.
Qualifying VTE diagnoses, pregnancy exclusions,
and progestogen use were assessed by year to evaluate
secular trends and similar ascertainment between
ICD-9 and ICD-10 codes. For each of the seven
progestogens of interest, the primary outcome was the
odds of incident acute VTE comparing current users
with noncurrent users of any progestogen
(Table 1).28,30,35 Crude odds ratios were calculated
by conditional logistic regression, adjusted for year
of birth and index date by study design. The final
multivariable model for each progestogen addition-
ally adjusted for all 16 VTE risk factors previously
described. Other studies have variably adjusted for
VTE risk factors even when individual covariates fail
to significantly modify the measure of associa-
tion.8,9,14,16,28 To aid in clinical application of the find-
ings, estimates of the absolute risks of VTE were
calculated as excess VTEs per 10,000 exposed women
at both ends of the reproductive age range for all
associations with an adjusted odds ratio (aOR) of at
least 2.0.1,39,40
Secondary analyses evaluated the effect of vary-
ing dose and chronicity within exposure to individual
progestogens (Table 1), adjusted for the same covari-
ates as the primary analysis. For each oral progesto-
gen, weighted average daily dose was assessed as a
categorical and continuous variable in conditional
logistic regression models. The categorical model
determined odds of VTE for low-dose, standard-dose,
Progestogens and Venous Thromboembolism 479
 Table 1. Exposure Characteristics

Category Term Definition

Exposure windows* Current use Exposure within 28 d before the index date (primary analysis)
Recent use Exposure within 84 d before the index date
Prior use Exposure within 85 through 365 d before the index date
Noncurrent use Cannot have any progestogen exposure within 28 d before the index date (reference
for primary analysis)
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Dose Weighted average The cumulative prescribed dose within recent use averaged over the interval from
daily dose start of exposure until the index date (maximum of 84 d)
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Low category Weighted average daily dose less than half the standard daily dose of each oral
progestogen
Standard category Weighted average daily dose between half and less than double the standard daily
dose of each oral progestogen
High category Weighted average daily dose greater than or equal to double the standard daily dose
of each oral progestogen
Chronicity New users All exposure occurs within no more than 84 d before the index date (ie, no prior use)
and meets current use criteria
Chronic users Exposure meets both prior use and current use criteria
Former users Exposure meets prior use but not current use criteria
Nonusers Cannot have any progestogen exposure that meets criteria for current use or prior use
(reference only for chronicity analysis)
* Current, recent, and prior use definitions are not affected by progestogen exposure or absence of exposure outside of its time window (eg,
exposures may continue beyond the index date).

and high-dose users compared with noncurrent users of
any progestogen (Table 1). The continuous model deter-
mined the change in odds of VTE for increasing
weighted average daily dose. Units were set at half of
the most commonly prescribed tablet of that progestogen
per day. Users with more than one recent progestogen
exposure and prescriptions with missing dose informa-
tion or with quantities less than one were excluded from
this analysis. Chronicity was assessed for all progestogens
by operationalizing exposure as a four-level categorical
variable combining current use and prior use variables
(Table 1) in conditional logistic regression models. For
each progestogen, comparisons were made between new,
chronic, former, and nonusers.
Finally, we planned two sensitivity analyses. To
assess for misclassification bias from inclusion of false-
positive VTE diagnoses, the primary analysis was
repeated after excluding inpatient women in the case
group without a corroborating anticoagulation pre-
scription. The primary analysis was also repeated with
an extended exposure time window comparing recent
progestogen use to nonrecent use to assess for mis-
classification from delayed use and to allow for
comparisons to prior literature.14
For all models, significance was set at P,.01 to
allow for multiple comparisons in the primary analy-
sis. Adjusted odds ratios were calculated with 99%
CIs. We considered secondary analyses to be
hypothesis-generating. A prespecified sample size cal-
culation was performed, with 90% power to detect an
association with an odds ratio of at least 2.0 at a fre-
quency of current use of each progestogen of at least
0.1% among women in the control group. Reliable
estimates of frequencies for noncontraceptive proges-
togens were not available. The entire available sample
was used because it was less than the target of 24,252
women with VTE. All analyses were performed using
SAS 9.4. This study using de-identified data was ex-
empted from review by the University of Chicago
Biological Sciences Division Institutional Review
Board.
RESULTS
Of 50,692 individuals with a qualifying VTE diagnosis
and adequate continuous enrollment, 21,405 women in
the case group matched 1:5 by year of birth and index
date to 107,025 women in the control group remained
after exclusions (Fig. 1). Characteristics of all qualifying
acute VTE diagnoses by type and source are provided
in Appendix 2, available online at http://links.lww.
com/AOG/C813. We did not see abrupt changes in
ascertainment of VTE or pregnancy diagnoses at the
transition from ICD-9 to ICD-10 codes (Appendix 3,
available online at http://links.lww.com/AOG/C813).
Characteristics of women in the case group and women
in the control group are provided in Table 2. Sixty
percent of the study population was aged 40–49 years
at the index date. Women in the case group and
women in the control group were significantly different
in all other covariates, with 66.3% of women in the case

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© 2022 by the American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
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Fig. 1. Case group and matched control group selection flow diagram. VTE, venous thromboembolism.
Cockrum. Progestogens and Venous Thromboembolism. Obstet Gynecol 2022.

group having one or more VTE risk factors compared
with 25.4% of women in the control group (P,.001).
Frequency of current use of any progestogen was 4.1%
and 2.4% for women in the case group and women in
the control group, respectively (P,.001), when com-
bining single and mixed use. Current use of LNG-
IUD, oral norethindrone, and etonogestrel implant
increased during the study period, and current use of
other progestogens remained stable (Appendix 3,
http://links.lww.com/AOG/C813).
The odds of VTE associated with current use of
each progestogen, compared with noncurrent use of
any progestogen, are provided in Figure 2. Use of the
higher-dose progestogens demonstrated significantly

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© 2022 by the American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
 Table 2. Characteristics of Women in the Case Group With Acute Incident Venous Thromboembolism and
Women in the Matched General Population Control Group

Characteristic Case Group (n521,405) Control Group (n5107,025)

Age (y) 42 (35–46) 42 (35–46)

Age group (y)
15–24 1,806 (8.4) 9,049 (8.5)
25–34 3,118 (14.6) 15,555 (14.5)
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35–39 3,647 (17.0) 18,277 (17.1)

40–44 5,692 (26.6) 28,436 (26.6)
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45–49 7,142 (33.4) 35,708 (33.4)

Comorbidities
Obesity (BMI 30 or higher) 4,451 (20.8) 7,882 (7.4)
History of smoking 1,789 (8.4) 3,059 (2.9)
Atherosclerotic cardiovascular disease 1,772 (8.3) 1,496 (1.4)
Hypertension 5,740 (26.8) 13,068 (12.2)
Congestive heart failure 729 (3.4) 333 (0.3)
Chronic kidney disease 806 (3.8) 432 (0.4)
Rheumatoid arthritis 363 (1.7) 706 (0.7)
Systemic lupus erythematous 641 (3.0) 655 (0.6)
Inflammatory bowel disease 464 (2.2) 574 (0.5)
Cancer (with exclusions)* 1,007 (4.7) 406 (0.4)
Hemiplegia or paraplegia 337 (1.6) 143 (0.1)
Hypercoagulable state 332 (1.6) 101 (0.1)
Superficial venous thrombosis 359 (1.7) 57 (0.1)
Varicose veins 610 (2.9) 807 (0.8)
Exposure
History of surgery or lower extremity 6,919 (32.3) 6,056 (5.7)
fracture (within 180 d before index)
History of hospitalization, excluding 4,894 (22.9) 2,313 (2.2)
index encounter (within 180 d before index)
Current user of a single progestogen† 836 (3.9) 2,533 (2.4)
Current user of multiple progestogens† 15 (0.1) 19 (0.02)
Recent user of a single progestogen‡ 990 (4.6) 2,983 (2.8)
Recent user of multiple progestogens‡ 27 (0.1) 34 (0.03)
* Excludes non-melanoma skin cancer, and also excludes breast and uterine cancer by study design.
BMI, body mass index.
Data are median (interquartile range) or n (%).
†
Current use is defined as exposure that occurs within 28 days before the index date.
‡
Recent use is defined as exposure that occurs within 84 days before the index date.

increased adjusted odds of VTE (oral medroxyproges-
terone acetate: aOR 1.98, 99% CI 1.41–2.80; oral
norethindrone acetate: aOR 3.00, 99% CI 1.96–
4.59; DMPA: aOR 2.37, 99% CI 1.95–2.88), whereas
low-dose oral norethindrone use was associated with
significantly reduced adjusted odds of VTE (aOR
0.57, 99% CI 0.43–0.76). Use of other progestogens
was not significantly different from nonuse (LNG-
IUD: aOR 0.72, 99% CI 0.50–1.05; etonogestrel
implant: aOR 1.09, 99% CI 0.66–1.82; oral progester-
one: aOR 1.07, 99% CI 0.66–1.73). All 16 VTE risk
factors included in the multivariable models were
independently associated with VTE. The conditional
logistic regression model for oral norethindrone ace-
tate is provided as a representative example (Appen-
dix 2, http://links.lww.com/AOG/C813). Odds ratios
for covariates included for adjustment differed by less
than 10% between all models.
In estimates of absolute risk (99% CI) for women
aged 20–24 years, current use of oral norethindrone
acetate was associated with seven (3–13) excess VTEs
per 10,000 exposed women and current use of DMPA
was associated with five (3–7) excess VTEs per 10,000
exposed women. For women aged 45–49 years with a
higher baseline VTE incidence, current use of oral
norethindrone acetate was associated with 12 (6–22)
excess VTEs per 10,000 exposed women and current
use of DMPA was associated with eight (6–11) excess
VTEs per 10,000 exposed women.
As shown in Table 3, most oral progestogen users
were exposed to low- or standard-weighted average
daily dose (median, interquartile range): 97% of oral

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© 2022 by the American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
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Fig. 2. Current use of progestogens and odds of venous thromboembolism (VTE). *Exposures are listed using a progestogen
dose hierarchy by Bergendal et al, modified to incorporate noncontraceptive progestogens (lowest to highest: levonorgestrel
intrauterine device [LNG-IUD], oral norethindrone [NET], etonogestrel implant [implant], oral progesterone [prog], oral
medroxyprogesterone acetate [MPA], oral norethindrone acetate [NETA], depot medroxyprogesterone acetate [DMPA]).
†Referent group for each conditional logistic regression model is noncurrent users of any progestogen (ie, no progestogen

use within 28 days before index date) (n5125,027; case group: n520,554, control group: n5104,473). The crude model
was adjusted for year of birth and index date by study design. The fully adjusted model additionally included 16 VTE risk
factors: obesity (body mass index 30 or higher), history of smoking, atherosclerotic cardiovascular disease, hypertension,
congestive heart failure, chronic kidney disease, rheumatoid arthritis, systemic lupus erythematous, inflammatory bowel
disease, cancer (with exclusions), hemiplegia or paraplegia, hypercoagulable state, superficial venous thrombosis, varicose
veins, history of surgery or lower extremity fracture within 180 days before index date, and history of hospitalization within
180 days of index date. ‡P,.01. §P,.001. OR, odds ratio.
Cockrum. Progestogens and Venous Thromboembolism. Obstet Gynecol 2022.

norethindrone users (0.34 mg/day, 0.28–0.35), 83% of analysis (Appendix 2, http://links.lww.com/AOG/

oral progesterone users (94.1 mg/day, 53.3–168.6),
95% of oral medroxyprogesterone acetate users
(3.45 mg/day, 1.71–7.63), and 86% of oral norethin-
drone acetate users (4.68 mg/day, 2.51–6.33). In mod-
els where progestogen exposure was represented by
weighted average daily dose as a continuous variable
(Appendix 2, http://links.lww.com/AOG/C813),
increasing oral norethindrone acetate and oral me-
droxyprogesterone acetate doses were directly pro-
portional to adjusted odds of VTE: +22% (aOR 1.
22, 99% CI 1.05–1.41) for each 2.5-mg/day increase
in oral norethindrone acetate and +19% (aOR 1.19,
99% CI 1.05–1.34) for each 5-mg/day increase in oral
medroxyprogesterone acetate. Increasing oral noreth-
indrone dose was inversely proportional to adjusted
odds of VTE. We did not find an association between
increasing oral progesterone dose and VTE. Models
of weighted average daily dose as a categorical vari-
able (Table 3) were limited by small sample sizes but
reflected the results of the continuous model. Com-
parisons of chronicity by a four-level categorical vari-
able broadly reflected the associations in the primary
C813).
In the sensitivity analysis excluding potentially
false-positive VTE diagnoses, 4,374 (35.6%) of
12,276 inpatient women in the case group did not
have a corroborating new anticoagulation prescrip-
tion (Appendix 2, http://links.lww.com/AOG/
C813). Only the aORs for current use of oral nor-
ethindrone acetate and DMPA were changed by
more than 10% and both increased (aOR 3.34,
99% CI 2.08–5.35; and aOR 2.66, 99% CI 2.15–3.
31, respectively). In the sensitivity analysis using
the extended exposure window of recent use
(Appendix 2, http://links.lww.com/AOG/C813),
all aORs decreased, but only the estimate for oral
norethindrone acetate decreased by more than 10%
(aOR 2.65, 99% CI 1.82–3.87).
DISCUSSION
We found that the association of current use of
progestogens and VTE was dependent on the type
and dose of progestogen. Use of higher-dose proges-
togens (oral medroxyprogesterone acetate, oral nor-

VOL. 140, NO. 3, SEPTEMBER 2022 Cockrum et al Progestogens and Venous Thromboembolism 483

© 2022 by the American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
 Table 3. Oral Progestogen Exposure (Categorical) Modeled by Weighted Average Daily Dose

Odds of VTE with Recent Progestogen Use vs

Nonrecent Use of Any Progestogen
Crude OR Adjusted OR
Progestogen Dose Category Recent Users* (99% CI)† (99% CI)‡

NETA Nonuser 124,392 (99.80) Ref Ref

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Low (less than 2.5 mg/d) 58 (0.05) 2.68 (1.32–5.47)§ 2.27 (1.04–4.97)k
Standard (2.5–less than 10 mg/d) 152 (0.12) 3.71 (2.43–5.67)§ 2.78 (1.69–4.57)§
CywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 02/21/2024

High (10 mg/d or greater) 34 (0.03) 4.00 (1.64–9.74)§ 2.76 (0.98–7.81)

MPA Nonuser 124,392 (99.57) Ref Ref
Low (less than 5 mg/d) 342 (0.27) 1.64 (1.18–2.27)§ 1.37 (0.95–1.98)
Standard (5–less than 20 mg/d) 169 (0.14) 3.28 (2.18–4.92)§ 2.66 (1.67–4.26)§
High (20 mg/d or greater) 25 (0.02) 4.00 (1.42–11.3)§ 2.27 (0.67–7.67)
Prog Nonuser 124,392 (99.72) Ref Ref
Low (less than 50 mg/d) 74 (0.06) 1.52 (0.75–3.10) 1.56 (0.71–3.46)
Standard (50–less than 200 mg/d) 217 (0.17) 1.12 (0.71–1.76) 0.92 (0.54–1.58)
High (200 mg/d greater) 60 (0.05) 2.01 (0.96–4.21) 1.54 (0.63–3.79)
NET Nonuser 124,392 (99.22) Ref Ref
Low (less than 0.175 mg/d) 107 (0.09) 0.90 (0.45–1.80) 0.50 (0.22–1.12)
Standard (0.175–less than 0.7 mg/d) 837 (0.67) 0.94 (0.73–1.20) 0.58 (0.44–0.77)§
High (0.7 mg/d or greater) 22 (0.02) 0.24 (0.02–3.40) 0.31 (0.02–4.38)
VTE, venous thromboembolism; OR, odds ratio; Ref, reference; NETA, oral norethindrone acetate; MPA, oral medroxyprogesterone acetate;
Prog, oral progesterone; NET, oral norethindrone.
* Sample sizes were smaller than in binary progestogen exposure models due to additional exclusions for multiple progestogen use, missing
dose information, or prescribed metric quantities less than 1 (NETA: n5124,636; MPA: n5124,928; Prog: n5124,743; NET:
n5125,358).
†
Adjusted for year of birth and index date by study design.
‡
Adjusted for year of birth and index date by study design and for 16 VTE risk factors: obesity, history of smoking, atherosclerotic
cardiovascular disease, hypertension, congestive heart failure, chronic kidney disease, rheumatoid arthritis, systemic lupus
erythematous, inflammatory bowel disease, cancer (with exclusions), hemiplegia or paraplegia, hypercoagulable state, superficial
venous thrombosis, varicose veins, history of surgery or lower extremity fracture within 180 days before index date, and history of
hospitalization within 180 days of index date.
§
P,.001.
k
P,.01.

ethindrone acetate, and DMPA) was significantly
associated with increased odds of VTE compared
with nonuse, whereas use of lower-dose progestogens
(LNG-IUD, oral norethindrone, etonogestrel implant,
and oral progesterone) was not significantly different
from nonuse or had reduced odds of VTE. The
importance of progestogen type and dose is supported
by the associations for LNG-IUD and DMPA at the
extremes of systemic dose, because both can be used
for contraception and to treat menstrual disor-
ders.19,20 This study provides the first adequate assess-
ments for use of the contraceptive etonogestrel
implant and noncontraceptive progestogens (oral pro-
gesterone, oral medroxyprogesterone acetate, and or-
al norethindrone acetate). To do so, it used a larger
sample size than the sum of all relevant studies iden-
tified in recent systematic reivews.4,6
Compared with those studies, we performed the
first exploration of varying progestogen dose and
chronicity.4,6 Modeling oral progestogen exposure by
weighted average daily dose for oral norethindrone
acetate and oral medroxyprogesterone acetate sug-
gested a dose–response relationship with VTE,
though the categorical dose model was limited by
wide CIs. In the chronicity model, we expected new
users to demonstrate a stronger association with VTE
than chronic users due to depletion of susceptibles,
but these groups were only significant different for
oral norethindrone.41 The effect size was as expected
for oral norethindrone acetate but much smaller for
DMPA and oral medroxyprogesterone acetate. We
also expected associations with VTE would not persist
after progestogen discontinuation. Former users and
nonusers were not significantly different for oral
norethindrone acetate and oral medroxyprogesterone
acetate, but they were significantly different for
DMPA (possibly due to its long duration) and oral
norethindrone. Future research could be powered to
evaluate these associations and incorporate dosing
pattern.
Progestogens as a class have not been associated
with acute prothrombotic changes, but effects may

484 Cockrum et al Progestogens and Venous Thromboembolism OBSTETRICS & GYNECOLOGY

© 2022 by the American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
 vary by type.33,42–45 Oral norethindrone and oral nor-
ethindrone acetate are uniquely metabolized to ethin-
yl estradiol at 0.2–1% of the orally administered
dose.46–48 Approved dosing for oral norethindrone
acetate at 5–15 mg/day approximates at least 10–30
micrograms/day of oral ethinyl estradiol, typical con-
traceptive doses. Medroxyprogesterone acetate (oral
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medroxyprogesterone acetate and DMPA) upregu-
lates thrombin receptor expression through its potent
CywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 02/21/2024
glucocorticoid activity.49 Clinical studies have found
dose-dependent increases in VTE risk associated with
glucocorticoid use.50,51 Progesterone and etonogestrel
also potentiate thrombin-induced procoagulant activ-
ity but have much lower affinity and activity at the
glucocorticoid receptor.37,52,53 Additional research is
needed on progestogen-mediated prothrombotic
effects at relevant doses and with novel types (eg,
dienogest).
This study has several limitations. First, 35.6% of
inpatient VTE diagnoses did not have a corroborating
anticoagulation prescription, similar to other stud-
ies.9,11,28,29 The sensitivity analysis confirmed that
such misclassification bias shifted the associations
towards unity, supporting the primary findings. Sec-
ond, exposure to oral progestogens was determined
by filled prescriptions without confirmation of actual
use. Third, though using a nationwide sample with
inpatient and outpatient women with VTE improved
generalizability, associations in this study may not
apply to individuals without private insurance or out-
side of the United States. Fourth, the data source did
not contain objective clinical data (eg, weight, family
history), and underascertainment of covariates cannot
be differentiated from absence of a condition. How-
ever, obesity and smoking status have not demon-
strated large confounding effects in the association
of hormone use and VTE.9,14,28 Fifth, these data were
not collected for research purposes and were subject
to misclassification, such as through conversion of
validated ICD-9 codes to ICD-10 codes.
Finally, these associations may have been con-
founded by indication due to contraindications for
alternatives (ie, estrogen) or conditions being trea-
ted.4,19 Because progestogens are used by women
with VTE risk factors, the associations for oral me-
droxyprogesterone acetate, oral norethindrone ace-
tate, and DMPA may remain inflated after
adjustment for measured confounders. Future stud-
ies on individual progestogens could construct more
balanced populations using propensity score match-
ing. This study design also did not permit direct
comparisons of VTE risk with users of combined
hormonal contraception because of differential bias
VOL. 140, NO. 3, SEPTEMBER 2022 Cockrum et al
© 2022 by the American College of Obstetricians
and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
in those populations (eg, selection bias, healthy user
bias). Our findings for LNG-IUD, oral norethin-
drone, and DMPA aligned closely with prior studies
that controlled for indications for use and other con-
founders not available in the data source, adding to
the external validity of the study.7,11,14,15,54 We also
assumed that benign conditions treated by proges-
togens were not causally linked to VTE. Menstrual
disorders were not found to have confounding
effects in one of the largest studies on hormone
use and VTE in women of reproductive age.9
Acknowledging that residual confounding cannot
be excluded, our study design benefited from a
large sample size, a well-suited data source, rigorous
classification, and sensitivity analyses of bias.
Although a dose–response relationship between
progestogens and VTE remains uncertain, we rec-
ommend that clinicians consider progestogen type
and dose to balance benefits, risks, and alternatives,
which differ for contraceptive and noncontraceptive
indications.
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PEER REVIEW HISTORY
Received March 10, 2022. Received in revised form May 20, 2022.
Accepted May 26, 2022. Peer reviews and author correspondence
are available at http://links.lww.com/AOG/C814.
Progestogens and Venous Thromboembolism 487