Review

European Journal of Preventive

Cardiology

Association between progestin-only 2018, Vol. 25(10) 1042–1052

! The European Society of
Cardiology 2018
contraceptive use and cardiometabolic
outcomes: A systematic review and Reprints and permissions:
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meta-analysis DOI: 10.1177/2047487318774847
journals.sagepub.com/home/ejpc

Marija Glisic1, Sara Shahzad2, Stergiani Tsoli3,4,

Mahmuda Chadni5, Eralda Asllanaj1, Lyda Z Rojas1,
Elizabeth Brown5, Rajiv Chowdhury2, Taulant Muka1
and Oscar H Franco1

Abstract
Aims: The association between progestin-only contraceptive (POC) use and the risk of various cardiometabolic out-
comes has rarely been studied. We performed a systematic review and meta-analysis to determine the impact of POC
use on cardiometabolic outcomes including venous thromboembolism, myocardial infarction, stroke, hypertension and
diabetes.
Methods and results: Nineteen observational studies (seven cohort and 12 case–control) were included in this
systematic review. Of those, nine studies reported the risk of venous thromboembolism, six reported the risk of
myocardial infarction, six reported the risk of stroke, three reported the risk of hypertension and two studies reported
the risk of developing diabetes with POC use. The pooled adjusted relative risks (RRs) for venous thromboembolism,
myocardial infarction and stroke for oral POC users versus non-users based on the random effects model were 1.06
(95% confidence interval (CI) 0.70–1.62), 0.98 (95% CI 0.66–1.47) and 1.02 (95% CI 0.72–1.44), respectively. Stratified
analysis by route of administration showed that injectable POC with a RR of 2.62 (95% CI 1.74–3.94), but not oral POCs
(RR 1.06, 95% CI 0.7–1.62), was associated with an increased risk of venous thromboembolism. A decreased risk of
venous thromboembolism in a subgroup of women using an intrauterine levonorgestrel device was observed with a RR
of 0.53 (95% CI 0.32–0.89). No effect of POC use on blood pressure was found, but there was an indication for an
increased risk of diabetes with injectable POCs, albeit non-significant.
Conclusions: This systematic review and meta-analysis suggests that oral POC use is not associated with an increased
risk of developing various cardiometabolic outcomes, whereas injectable POC use might increase the risk of venous
thromboembolism.

Keywords
Progestogen, progesterone, progestin-only pill, contraception, stroke, myocardial infarction, venous thromboembolism,
hypertension, type 2 diabetes, women, cardiometabolic risk
Received 26 January 2018; accepted 13 April 2018
3
Department of Population Health, London School of Hygiene and
Tropical Medicine, UK
4
Centre for Longitudinal Studies, University College London, UK (cur-
Introduction rent address)
5
A number of studies have debated the association Nuffield Department of Population Health, University of Oxford,
England
between combined oral contraceptive use and the risk
The first two and final two authors contributed equally.
of cardiometabolic outcomes,1–3 with some studies
Corresponding author:
Marija Glisic, Department of Epidemiology, Erasmus University Medical
1
Department of Epidemiology, Erasmus Medical Center, The Netherlands Center, Dr Molewaterplein 50, Office NA29-09, PO Box 2040, 3000 CA
2
Cardiovascular Epidemiology Unit, Department of Public Health and Rotterdam, The Netherlands.
Primary Care, University of Cambridge, Cambridge, England Email: [email protected]
Glisic et al. 1043

reporting an increased risk of venous thromboembol- developing various cardiometabolic outcomes such as
ism (VTE), stroke and myocardial infarction (MI) for MI, stroke, VTE, diabetes and hypertension.
users of combined oral contraceptives (COCs).3,4 COCs
can affect lipid profiles, carbohydrate metabolism,
haemostatic factors and thrombolysis, and this may Methods
be the pathway by which they affect the risk of develop-
ing various cardiometabolic outcomes.5–8. It has been
Data sources and search strategy
postulated that the increased risk of various cardiome- The Cochrane Handbook for Systematic Reviews of
tabolic outcomes is mainly attributed to the oestrogen Interventions and PRISMA and MOOSE guidelines
content of these contraceptives,9 while the role of were used to guide the conduct and reporting of this
exogenous progestins in modulating the oestrogenic review.20,21 We conducted a literature search of articles
effects remains controversial.10 Therefore, over the from the following electronic databases from the earliest
years the oestrogen content of combined oral contra- record to 16 January 2017: PubMed, Web of Science
ceptive pills has decreased and new oral contraceptives and EMBASE. The search strategy was built based on
with progestin-only content have been developed, the PICO strategy and followed the recommendations
which are considered to be safer.9 The type of progestin of the Cochrane Review for progestin-only pills.22
as well as the route of administration are important The following key words were searched: ‘progesterone
factors in predicting the risk of various cardiometabolic only pill’, ‘progesterone’, ‘progestin only’, ‘progestogen
outcomes. Progestins such as gestodene, norgestimate only’, ‘cardiovascular disease’, ‘heart disease’, ‘cerebro-
and desogestrel have been associated with a greater vascular disease’, ‘stroke’, ‘myocardial infarction’, ‘cor-
VTE risk than the older progestins (levonorgestrel, onary artery disease’, ‘venous thromboembolism’,
lynestrenol, norethisterone).11 Also, studies have ‘diabetes’ and ‘hypertension’. In addition, reference
reported an elevated risk of VTE with the use of lists of the included studies and relevant reviews,
depot medroxyprogesterone (DMPA), which has a rela- as well as studies that have cited these articles, were
tively higher dose of progestin.12,13 Weight gain is cited searched with Elsevier’s Scopus, the largest abstract
as a common side effect and is a major reason for dis- and citation database. The detailed master search strat-
continuation of DMPA.14 Previous studies have gener- egy is shown in Supplementary Figure 1.
ally found no association between the use of injectable During the first phase of screening, two reviewers
or implantable progestin-only contraceptives (POCs) evaluated the titles and abstracts against the inclusion
and the development of glucose intolerance;15 however, and exclusion criteria. For each potentially eligible
epidemiological evidence has suggested a possible study, two reviewers independently assessed the full
increased risk of diabetes among DMPA users.15 A text. In cases of disagreement, a decision was made
rise in blood pressure as a side effect of combined by consensus or, if necessary, a third reviewer was
oral contraceptives has been theorised to be the critical consulted.
mechanism for increased cardiovascular risk in women
on COCs; however, the evidence on the effect of POCs
Study selection and eligibility criteria
on blood pressure remains limited.16 To date, there is
scarce evidence on how POCs affect the various cardi- Studies were included if they met all of the following
ometabolic outcomes, which might be because of the inclusion criteria: (a) used a randomised trial, case–
low occurrence of chronic diseases among women of control, cohort (prospective or retrospective), or
reproductive age, and therefore low statistical power cross-sectional study design; (b) reported the presence
to estimate the reliable risk due to the usage of of a treatment arm featuring the use of POCs; (c)
POCs.16 Although few reviews have evaluated the role reported the use of progestin for the purpose of contra-
of POCs and the risk of VTE, stroke and MI,11,16–19 ception only; (d) collected data on the incidence of car-
these reviews have some limitations. They are focused diovascular disease (MI, stroke, heart disease, VTE
on specific outcomes (MI or VTE or stroke), include events), diabetes and hypertension; and (e) were based
only specific study designs (case–control only), search on human data only and reported odds ratio or relative
available literature only within a few databases and are risk (RR) comparing the use of POCs with non-users of
non-quantitative or largely non-systematic in nature. contraceptives.
Therefore, an updated and comprehensive quantitative
review is important, given the different types of cardi-
Data extraction
ometabolic outcomes that may be affected by POC use
by women of child-bearing age. Two reviewers independently extracted data and con-
This systematic review and meta-analysis aims to sensus was reached in the case of any inconsistency with
investigate the impact of POC use on the risk of involvement of a third reviewer. A piloted data
1044 European Journal of Preventive Cardiology 25(10)

extraction form was used. This included data on: study pooled. Heterogeneity was quantified using the I2 stat-
size; study design; baseline population; location; age at istic, classified as low (I2  25%), moderate (I2 > 25%
baseline; duration of follow-up; reported degree of and <75%), or high (I2  75%).28 In addition, the
adjustment; type of POC use; type and numbers of out- Q statistic was used to assess the presence of heterogen-
comes; how outcomes were ascertained; and reported eity. PQ statistic  0.05 was considered to indicate no sig-
risk ratios. In instances of multiple publications, the nificant heterogeneity among the included studies.
most up-to-date information was extracted. Publication bias was assessed through a funnel plot
and asymmetry was assessed using the Egger’s test.
It was not feasible to perform sensitivity analyses due
Assessing the risk of bias to the small number of included studies. All tests were
Bias within each individual study was evaluated by two two-tailed and P values of 0.05 or less were considered
independent reviewers using the validated Newcastle– significant. STATA 14 (Stata Corp, College Station,
Ottawa scale, a semi-quantitative scale designed to TX, USA) was used for all statistical analyses.
evaluate the quality of non-randomised studies.23
The assessment of study quality was based on the selec-
tion criteria of participants, comparability of cases and Results
controls, and exposure and outcome assessment.
Studies that received a score of nine stars were judged
Study identification and selection
to be at low risk of bias; studies that scored seven or A total of 9898 references were identified: 2688 from
eight stars were considered at medium risk; those that PubMed, 3198 from Web of Science, 460 from
scored six or less stars were considered at high risk of EMBASE and 3552 from the search in Elsevier’s
bias. Detailed information on the assessment of study Scopus (Figure 1). Of these, 5210 duplicates were
quality and risk of bias is provided in Supplementary removed, and 4290 were excluded after review of the
Tables 1 and 2. titles and abstracts, leaving 398 articles for full-text
screening. After full-text assessment 19 articles were
included in this review. Of these studies, two were
Patient involvement nested case–control studies, 10 case–control studies
Patients were not involved in our study. and seven cohort studies. No randomised clinical trial
was found. Nine studies reported the risk of VTE, six
studies reported the risk of MI, six reported the risk of
Statistical analysis stroke, three reported the risk of hypertension and two
We estimated the risk ratio of cardiovascular diseases studies reported the risk of developing diabetes.
(VTE, MI and stroke) for users of POCs versus non-
users in subgroups according to the route of adminis-
tration (oral, injectable and intrauterine). Based on
Characteristics of included studies
previous reports estimating the yearly incidence of In total, 19 studies were included in this review, includ-
those events to about 0.06% per year,24 we considered ing data from 62,088 women of which 11,930 women
that cardiovascular events had a low incidence (<10% reported using POCs. The majority of the included stu-
a year) in women aged less than 50 years taking oral dies were conducted in Europe (n ¼ 12) followed by the
contraceptives. For infrequent events, the RR and odds USA (n ¼ 5). In addition, there were two multi-country
ratio are considered equivalent measures of RR.25,26 studies. The age of participants ranged from 15 years to
For initial disease risks of 10% or less, even odds about 66 years. Fifteen studies reported on POCs
ratios of up to eight can reasonably be interpreted as administered orally, and five studies by injection,
RRs.27 For each study, we used the most adjusted RR implant or intrauterine device (IUD).
with its 95% confidence interval (CI) and we used the
inverse variance weighted method to combine RRs to
produce a pooled RR using random-effects meta-ana-
POC use and risk of VTE
lysis models, to allow for between-study heterogeneity. POC use and the risk of VTE were reported in nine
We also conducted sensitivity analyses using fixed articles,12,13,29–35 four of which were retrospective
effects models and we present the results in the forest case–control studies, two were nested case–control stu-
plots. Furthermore, when a study reported more than dies and three were cohort studies. The details on study
one risk estimate, the pooled RR was obtained using a participants can be found in Supplementary Table 3.
fixed-effects model. A narrative synthesis and construc- Eight studies investigated the risk of VTE with oral,
tion of descriptive summary tables were performed for two studies with intrauterine and three with injectable
those study outcomes that could not be quantitatively POCs. Therefore, we have estimated the fully adjusted
Glisic et al. 1045

Identification
Records identified through PubMed Additional records identified through Web of science,
searching EMBASE and Elsevier’s Scopus reference lists
(n = 2688) (n = 3198), (n = 460) and (n = 3552) respectively

Records after duplicates removed

(n = 4688)
Screening

Records screened Records excluded after review of

(n = 4688) the titles and abstracts
(n = 4290)

Full-text articles assessed for

eligibility Full-text articles excluded (n = 379) ,
with reasons:
Eligibility

(n = 398)
Study design not relevant (n = 239 )
Outcome not relevant (n = 74)
Results not reported for POC (n = 41)
Absence of a non-user comparison group (n = 15)
Old version of a study with recent update (n = 7)
Duplicates (n = 3)
Included

Studies by outcome:
VTE (n = 9)
MI (n = 6)
Studies included in quantitative Stroke (n = 6)
synthesis (meta-analysis) Diabetes (n = 2)
(n = 19) Hypertension (n = 3)

Figure 1. Flow diagram of studies included in the review.

(as reported in studies) risk ratio of VTE for POC POC formulation (levonorgestrel) was 0.53 (95% CI
users versus non-users in each subgroup according 0.32–0.89), I2 ¼ 10.7% and PQ statistic ¼ 0.29. On the
to the route of administration (oral, injectable and other hand, the RR of VTE for injectable progestin
intrauterine). formulation (DMPA) was 2.62 (1.74–3.94), I2 ¼ 0%
Pooled fully adjusted risk ratios, based on more than and PQ statistic ¼ 0.53 (Figure 2).
500 women using POCs and 176 VTE events, showed
no significant association of oral POC use with the risk
of VTE when comparing users with non-users (pooled
POC use and risk of MI
risk ratio 1.06, 95% CI 0.7–1.62). There was no evi- Six studies reported the risk of MI with POC use30,36–40
dence of high between-study heterogeneity for POC (Supplementary Table 4). Of those, five were case–
use and the risk of VTE in these studies (I2 ¼ 36.5% control studies and one was a cohort study. Five
and PQ statistic ¼ 0.14). Only three case–control studies studies reported RR after oral POC administration,
reported the risk of VTE with injectable (72 controls, two studies reported RR in women using progestin
78 cases) and two studies reported on intrauterine implants and one study reported RR of MI after inject-
(125 controls and 64 cases) progestin administration. able and intrauterine POC administration.
The pooled risk ratio of VTE for users of intrauterine The adjusted RR of MI for users of POCs versus
1046 European Journal of Preventive Cardiology 25(10)

Author, No. of cases ES (95% CI)

Location Study design POC type
year of publication in POC users

Oral
Barsou, 2010 USA case-control 3 MPA 1.20 (0.40, 3.63)
Bergendal, 2014 Europe case-control 61 Levonorgestrel 0.80 (0.40, 1.90)
Conard, 2004 Europe cohort 3 Chlormadinone acetate, 10mg 0.80 (0.20, 3.90)
Heinemann, 1999 Europe case-control 7 NA 0.68 (0.28, 1.66)
Lidegaard, 2012 Europe cohort 70 Norethisterone, Desogestrel 0.51 (0.23, 1.14)
Vaillant-Roussel, 2011 Europe cohort 7 NA 1.30 (0.50, 3.00)
Vasilakas, 1999 Europe case-control 4 Levonogestrel 3.40 (0.80, 7.10)
WHO, 1999 Worldwide case-control 21 d-Norgestrel 1.82 (0.79, 4.22)
Fixed-effects model (I-squared = 36.5%, p = 0.138) 1.04 (0.75, 1.44)
Random-effects model 1.06 (0.70, 1.62)

Intrauterine device
Bergendal, 2014 Europe case-control 61 Levonorgestrel 0.60 (0.40, 1.00)
Vlieg, 2010 Europe case-control 3 Levonorgestrel 0.30 (0.10, 1.10)
Fixed-effects model (I-squared = 10.7%, p = 0.290) 0.55 (0.36, 0.84)
Random-effects model 0.53 (0.32, 0.89)

Injectable POC
Bergendal, 2014 Europe case-control 47 Medroxyprogesterone acetate 2.20 (1.30, 4.00)
WHO, 1998 Worldwide case-control 11 Medroxyprogesterone acetate 2.19 (0.66, 7.26)
Vlieg, 2010 Europe case-control 20 Medroxyprogesterone acetate 3.60 (1.80, 7.10)
Fixed-effects model (I-squared = 0.0%, p = 0.527) 2.62 (1.74, 3.94)
Random-effects model 2.62 (1.74, 3.94)

Figure 2. The association between progestin-only contraceptive (POC) use and risk of venous thromboembolism by route of
administration. The summary estimates presented were calculated using random effects and fixed effects models. 95% confidence
interval (CI) (bars). P comes from Q statistics.

non-users varied from 0.5 to 3.5, none of the studies evidence to suggest that the use of POCs is associated
reporting a statistically significant association. Pooled with the risk of stroke (pooled risk ratio 1.02, 95% CI
results for the fully adjusted models, based on more 0.72–1.44) for the fully adjusted model (Figure 4).
than 150 women using POCs and 47 MI cases, There was no evidence of between-study hetero-
showed that there was no significant association of geneity for stroke risk and POP use (I2 ¼ 0% and
MI risk with those who used POCs orally versus PQ statistic ¼ 0.99). The pooled RR of stroke in women
those who did not use hormone therapy (pooled risk using POCs other than orally was 0.78 (95% CI 0.6–1),
ratio 0.98, 95% CI 0.66–1.47) (Figure 3). In addition, I2 ¼ 0% and PQ statistic ¼ 0.79.
there was no evidence of between-study heterogeneity
for POC use and risk of MI in these studies (I2 ¼ 0%
and PQ statistic ¼ 0.72). The pooled RR for MI in
POC use and risk of hypertension
the subgroup of women using progestin other than Only three cohort studies were found to report the
orally was 1.10 (95% CI 0.77–1.56), I2 ¼ 0% and impact of POC use with the risk of developing hyper-
PQ statistic ¼ 0.65. tension43–45 (Supplementary Table 6). A study by
Spellacy and Birk et al.43 followed 415 predominantly
American black women for 2 years and reported that
POC use and risk of stroke
those who used POCs had a significant drop in dia-
Six studies examined the association between POC stolic blood pressure (P < 0.05). However, most of the
use and the risk of stroke30,37,39–42 (Supplementary women in this study were 4 weeks postpartum, and
Table 5). Of those, five were case–control studies and subsequently using mini pills as a contraceptive
one was a cohort study. The adjusted RR of stroke for method, which might present a bias in case selection.
users of POCs versus non-users varied from 0.89 to 1.6, However, two studies44,45 of 119 and 593 participants,
none of the studies reporting a statistically significant respectively, reported that POC use had no significant
association. The summary measure from pooled ana- effect on blood pressure. These studies were limited by
lysis including 350 women using progestin contracep- small sample size, inadequate adjustment for confoun-
tives orally and 199 stroke events showed no significant ders and lost to follow-up bias.
Glisic et al. 1047

Author, No. of cases

Location Study design POC type ES (95 %CI)
year of publication in POC users

Oral

Dunn, 1999 UK Case-control 9 Progestogen 1.48 (0.60, 3.65)

Heinemann, 1999 Europe Case-control 7 NA 0.94 (0.31, 2.91)

Lidegaard, 2012 Europe Cohort 13 Norethindrone, Desogestrel 0.97 (0.56, 1.68)

Thorogood, 1991 UK Case-control 15 NA 0.50 (0.14, 1.83)

d-Norgestrel, Anorethidrate
WHO, 1999 Worldwide Case-control 3 0.98 (0.16, 5.97)
diproproinate, DI-Norgestrel, Norethisetrone

Fixed-effects model (I-squared = 0.0%, p = 0.761) 0.98 (0.66, 1.47)

Random-effects model
0.98 (0.66, 1.47)

Other

Petitti, 1998 USA Case-control 1 Levonorgestrel 3.50 (0.20, 56.50)

Lidegaard, 2012 Europe Cohort 33 Levonorgestrel 1.09 (0.71, 1.46)

WHO, 1999 Worldwide Case-control 1 DMPA 0.66 (0.07, 6.00)

Fixed-effects model (I-squared = 0.0%, p = 0.654) 1.10 (0.77, 1.56)

Random-effects model
1.10 (0.77, 1.56)

Figure 3. The association between oral progestin-only contraceptive (POC) use and risk of myocardial infarction by route of
administration. The summary estimates presented were calculated using random effects and fixed effects models. 95% confidence
interval (CI) (bars). P comes from Q statistics.

Author, No. of cases

Location Study design POC type ES (95% CI)
year of publication in POC users

Oral
Lidegaard, 1993 Europe Case-control 7 Progestogen 0.90 (0.40, 2.40)

Tzourio, 1995 Europe Case-control 1 Progestogen 1.10 (0.10, 10.30)

d-Norgestrel, Anorethidrate
WHO, 1998 Worldwide Case-control 54 1.07 (0.62, 1.86)
diproproinate, DI-Norgestrel, Norethisetrone
Heinemann, 1999 Europe Case-control 3 NA 1.60 (0.20, 10.70)

Lidegaard, 2012 Europe Cohort 134 Pooled 0.97 (0.56, 1.68)

Fixed-effects model (I-squared = 0.0%, p = 0.987) 1.02 (0.72, 1.44)

Random-effects model 1.02 (0.72, 1.44)

Other

Lidegaard, 2012 Europe Cohort 48 Levonogestrel 0.74 (0.55, 0.99)

Petitti, 1998 USA Case-control 1 Progestogen 1.10 (0.10, 9.20)

WHO, 1998 Worldwide Case-control 1 DMPA, Norethisterone 0.89 (0.53, 1.49)

oenanthate
Fixed-effects model (I-squared = 0.0%, p = 0.794) 0.78 (0.60, 1.00)

Random-effects model 0.78 (0.60, 1.00)

Figure 4. The association between oral progestin-only contraceptive (POC) use and risk of stroke by route of administration. The
summary estimates presented were calculated using random effects and fixed effects models. 95% confidence interval (CI) (bars). P
comes from Q statistics.

developing type 2 diabetes (T2D). A case–control

POC use and risk of diabetes
study by Kim et al.46 reported the association of POC
We found two epidemiological studies that investigated use and the risk of developing T2D in a health centre in
the association between POCs and the risk of the USA (Supplementary Table 7). Diabetic cases
1048 European Journal of Preventive Cardiology 25(10)

(n ¼ 284) and non-diabetic controls (n ¼ 570) were A study that contributed most to the summary statistic
matched by age. It was found that users of POCs for DMPA and the risk of VTE excluded women in
(DMPA) were at an increased risk of developing dia- highest risk of VTE (personal history of VTE);12 there-
betes compared to those who used combined pills (oes- fore, it is less likely that the effect observed on injectable
trogen–progestogen), odds ratio 3.6 (95% CI 1.6–7.9), progestin is due to confounding by indication. POC
after adjusting for age and body mass index (BMI). intake causes a decrease in sex hormone-binding globu-
When compared with no history of hormonal contra- lin, which is a marker of venous thrombosis risk, and
ceptive use, POCs were still associated with the risk of this effect varies with the dose and type of progestogen
developing diabetes, odds ratio 2.1 (95% CI 1.03–4.2), used.48,49 Indeed, the plasma concentration of levonor-
when adjusted for age, BMI and parity. However, fur- gestrel with IUD ranges between 74 and 166 pg/mL,50
ther adjustment for gestational diabetes diagnosed after while after an intramuscular injection of 150 mg
contraceptives given attenuated and abolished the asso- of DMPA, the peak plasma concentration is 2500–
ciation, odds ratio 1.6 (95% CI 0.77–3.5). In a cohort 7000 pg/mL and remains greater than 430 pg/mL at 3
study,47 Norplant users (n ¼ 7977) were prospectively months.51,52 Also, progestins may express prothrombo-
compared with age-matched, non-hormonal IUD tic properties by modulation of protein C resistance,53
users (n ¼ 6625) and women who underwent sterilisa- by affecting the cellular expression of tissue factor
tion (n ¼ 1419). Twelve T2D cases were identified – nine and circulating tissue factor pathway inhibitor.54,55
in Norplant initiators (eight current users), two in IUD The third generation progestins (e.g. desogestrel) are
initiators (three current IUD users) and one in a ster- suggested to be more prothrombotic than earlier for-
ilised woman. The crude incidence rate was higher in mulations such as levonorgestrel or norethisteron.11
current Norplant users compared with controls, but the Levonorgestrel does not increase activated protein C
crude and adjusted rate ratios for Norplant users com- resistance, suggesting that this contraceptive does not
pared with controls were not significantly different. have a prothrombotic effect.53 While, for instance, in a
After adjusting for clinic, age and body weight, the cur- mouse model of vascular injury, medroxyprogesterone
rent implant users did not have a significantly higher increased thrombin formation and changes in vascular
incidence of T2D compared with the group using IUD gene expression, resulting in altered plaque matrix
or sterilisation, RR 2.4 (95% CI 0.7–8.1). either alone and in combination with oestradiol.56
A previous meta-analysis of six case–control studies
reported that there was no increase in the MI risk with
Study quality and publication bias
POC use.17 In our meta-analysis we excluded one of the
Three studies were classified as having a low risk of studies included in previous estimates, as it was inves-
bias, five as having a medium risk of bias and the rest tigating the effect of COCs (contained up to 50 mg of
were classified as having a high risk of bias. We did not oestrogen combined with a fixed dose of progestin),57
find evidence for publication bias from the funnel plots and was not a progestin-only pill; however, our results
of VTE, MI and stroke, as shown in Supplementary were in line with previous findings. The result was simi-
Figure 2. lar according to the route of administration, including
implant, injectable and oral POCs. Furthermore, our
findings are in line with a previous meta-analysis of
Discussion six case–control studies18 showing that POC use had
Overall, the available body of literature suggests that no significant effect on the risk of developing stroke.
the use of oral POCs is not associated with an excess Similarly, a systematic review looking at the association
risk of VTE, MI, stroke and hypertension. We found of POC use with high blood pressure also concluded
limited evidence that DMPA is associated with an that POC use does not affect diastolic and systolic
increased risk of VTE, while intrauterine application blood pressures.16 However, all of the included studies
of levonorgestrel was associated with a decreased risk were written in the 1970s and 1980s; therefore, they
of VTE. There was, also, an indication for an increased have investigated the first and second generations of
risk of diabetes with injectable POCs, albeit non- POCs, while the information on the third generation
significant. of progestins is lacking. Furthermore, an important
Our findings suggest no effect on VTE risk after oral limitation of these studies is the fact that they investi-
POCs and a decreased risk of VTE in a subgroup of gated POC use in normotensive women, yet future stu-
women using an intrauterine levonorgestrel device with dies should investigate the effects of POCs on blood
RR 0.53 (95% CI 0.32–0.89). However, the subgroup pressure in women with a history of hypertension.
analysis based on three studies,13,34,40 including 78 VTE A case–control study conducted among Navajho
events, showed a 2.6-fold increased risk of VTE for women showed that use of injectable POCs significantly
injectable progestin users compared to non-users. increased the risk of developing T2D when adjusted for
Glisic et al. 1049

age, BMI and parity; however, after further adjustment of POC use with multiple cardiometabolic outcomes
for gestational diabetes diagnosed after contraceptives such as VTE, MI, stroke, hypertension and diabetes.
given, the association was attenuated and not any more Nevertheless, there are number of limitations to this
significant.46 Women with gestational diabetes are at review. First, typical with any literature-based review,
higher risk of developing T2D, and women who used it is possible that both measured and unmeasured pub-
DMPA were significantly more likely to have a history lication bias can limit our overall findings. Although
of gestational diabetes.46 Therefore, it might be that evaluations with the conventional funnel plots and
gestational diabetes is on the pathway between POC Egger test estimates indicate minimal publication bias,
use and T2D development, which needs further inves- these approaches are limited by a qualitative assessment
tigation. Nevertheless, a study conducted in breast- reliant on visual inspection and the fact that the major-
feeding Latina women with previous gestational ity of these assessments were based on a limited number
diabetes mellitus demonstrated that oral POCs were of studies. Thus we cannot exclude the possibility of
associated with an increased risk of diabetes compared publication bias coming from the underreporting of
with an equal use of low-dose combination oral contra- negative findings (increased risk of cardiovascular out-
ceptives, indicating that if an association between POC comes with POC use). Such a scenario would lead
use and diabetes exists pathways other than gestational towards null findings and an underestimation of our
diabetes may be present.58 In this study, however, low- findings. The studies included in this review were
dose progestin and COCs were not associated with risk limited by study design and methodology: (a) all studies
of diabetes.58 The mechanism linking POC use with a were observational in nature and thus prone to bias
potential increased risk of diabetes is unknown. A pos- and confounding; (b) they had small numbers of
sible mechanism might be the adverse effect that POC participants using POCs, which explains the wide CIs
use has on obesity, which is an important risk factor for of some of the studies; and (c) studies did not specify
diabetes.46 The 2016 Cochrane review investigated the the type and dosage of POCs or the type and
association between POC use and weight changes.59 dosage of POCs varied considerably. Also, even
Although the actual mean weight gain was generally though the prevalence of intermediate risk factors
low (<2 kg for most studies) for 6–12 months of for cardiovascular disease is low among women
follow-up, the effect on weight varied with different of reproductive age, 10% of women aged 18–44 years
formulations and routes of POC administration, being have high blood pressure, while 15% of women
more pronounced with DMPA.14,60–62 Furthermore, aged 20–45 years have high cholesterol, also 3%
using contraception reduces the numbers of pregnan- of women of reproductive age have T2D.65,66
cies, which is also considered to be a risk factor for Although the majority of studies included in our
developing diabetes.46 Also, a decrease in sex- review adjust for potential confounding and intermedi-
hormone-binding globulin is associated with injectable ate cardiovascular risk factors, they do not adjust
DMPA,63 and low circulating levels of sex hormone- for medication use (e.g. statins, antihypertensive
binding globulin are a strong predictor of the risk of medications). Therefore, future studies should take
T2D in women and men.64 The other possibility is that this into account when investigating the risk of diabetes
women taking COCs compared to those receiving with POC use.
DMPA are healthier and have a lower risk of develop-
ing T2D.46 Indeed, a systematic review on studies in
non-diabetic women based on six studies investigating
Implications for policy and future research
DMPA use reported an elevation of insulin concentra- European guidelines on cardiovascular disease preven-
tion (compared with baseline before DMPA) at 2–3 tion in clinical practice have emphasised the role of the
hours after the glucose challenge;15 however, most of cardiologist in screening for cardiovascular disease risk
the studies included in the review did not find any effect factors and assessing the baseline cardiovascular risk
of injectable contraceptives on glucose concentrations before advising the type of contraceptives to be
in lean glucose-tolerant women. Studies that reported used.67 US medical eligibility criteria for contraceptive
increased glucose were performed in subjects who had use advocates the use of POCs for women at high risk
greater baseline body weight or had a longer duration of cardiovascular disease,68 which may be a safe recom-
of POC use.15 mendation as also supported by our findings of no
association between oral POC use and VTE, MI and
stroke in women in general. Although the US medical
Strengths and limitations
eligibility criteria for contraceptive use68 recognises
Our results are consistent with previously published a previous history of MI and stroke as well as hyper-
reviews;11,16–19 however, this is the first systematic tension as contraindications for injectable POC use,
review and meta-analysis that looks at the association a previous history of VTE is not recognised
1050 European Journal of Preventive Cardiology 25(10)

as a contraindication for DMPA. Therefore, based on or approval of the manuscript. RC, SS, ST, MC, LZR and EB
our findings of an increased risk of developing VTE and have nothing to disclose.
present indication of an increased risk of T2D, further
investigation is required in order to rule out potential Funding
harmful effects of DMPA in these women. The author(s) received no financial support for the research,
authorship, and/or publication of this article.
Conclusions
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