https://orcid.org/0000-0002-8682-4072
Figures
Abstract
Objective
To evaluate the safety and effectiveness of hormonal contraceptives compared to non-hormonal methods or no contraception in hypertensive women seeking future fertility.
Data sources
Searches were conducted in Medline, Embase, CENTRAL, and LILACS (September –October, 2022), with updates on September, 2023, and August, 2024. Clinical trial records, regulatory agencies, and gray literature were also consulted (June, 2022; August, 2023; September, 2024).
Methods
Eligible studies that assessed safety (major adverse cardiovascular events, pelvic inflammatory disease, vaginal infections, loss of fertility, discontinuation, worsening hypertension, peripheral arterial disease, venous thromboembolism, weight gain, liver or kidney function changes) or effectiveness (pregnancies/Pearl index) of hormonal contraceptives in hypertensive women. Eligible designs included clinical trials, cohort and case control studies, case series, case reports, and adverse event data. Two reviewers independently screened titles/abstracts, reviewed full texts, selected studies, extracted data, and assessed bias (ROBINS-I: cohorts), methodological quality (Newcastle Ottawa: case-control), and critical appraisal (Joanna Briggs Institute: case series). Certainty of evidence was evaluated using GRADE. Evidence was synthesized quantitatively and qualitatively by contraceptive and outcome.
Results
Of 32,225 records screened, 17 studies were included. Combined oral contraceptives may increase hemorrhagic cerebrovascular disease (OR: 1.64 (95% CI 1.08–2.50, certainty: low). Evidence is very uncertain about their effects on preventing pregnancies, and safety related to ischemic cerebrovascular disease, myocardial infarction, venous thromboembolism, weight gain, hypertension, kidney function, and lipid profile. Similarly, the effects of progestin-only pills, injectables, and vaginal rings on cardiovascular and metabolic outcomes remain highly uncertain. Certainty is also very low for combined oral contraceptives or progestogen-only pills regarding cerebrovascular disease, myocardial infarction (OR: 1.15, 95% CI 0.60–2.19), and peripheral arterial disease.
Citation: Losada-Trujillo N, Estrada-Orozco K, Velasco-Lancheros OJ, Ramírez-Vargas BA, Burgos-Cárdenas ÁJ, González-Caicedo PA, et al. (2026) Safety and effectiveness of hormonal vs non-hormonal or no contraception in women with hypertension and future fertility desire: A broad-scope systematic review. PLoS One 21(3): e0345959. https://doi.org/10.1371/journal.pone.0345959
Editor: Noor Jahan, Dow University of Health Sciences, PAKISTAN
Received: July 12, 2025; Accepted: March 12, 2026; Published: March 31, 2026
Copyright: © 2026 Losada-Trujillo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All data underlying the findings of this systematic review are fully available without restriction. The files containing the articles screened by title and abstract from the databases, provided in standard reference formats (.ris, .bib, .csv, and .enw), as well as the presentation summarizing the study, are available in the Zenodo repository (https://doi.org/10.5281/zenodo.18906040; https://doi.org/10.5281/zenodo.18906289). Additional materials supporting the study, including search strategies, data extraction forms, quality assessment results, and supplementary tables, are provided as Supporting information files accompanying this paper.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
1. Introduction
Global life expectancy has increased as well as chronic non-communicable diseases [1] and the age of women at childbirth [2]. In 2021, the Organization for Economic Cooperation and Development (OECD) reported an average childbirth age of 30.9 years in its member countries [3]. Higher age raises the risk of chronic diseases [1], and pregnancy-related complications [4]. In 2019, in women of reproductive age (15–49 years), the main causes of death from non-communicable diseases worldwide were: neoplasms (19.66%), cardiovascular diseases (15.03%), digestive diseases (5.39%) and diabetes/chronic kidney disease (4.53%) [1]. Hypertension is the main cardiovascular risk factor in this population [1], which is associated with Major Adverse Cardiovascular Events (MACE) (cardiovascular death, acute myocardial infarction (AMI), cerebrovascular disease (CVD), unstable angina, coronary revascularization, acute heart failure or worsening of heart failure, and transient ischemic attack (TIA) [5,6]). In 2019, ischemic heart disease caused 6.31% of non-communicable disease deaths, while ischemic CVD accounted for 0.75% of deaths in women of reproductive age [1].
Studies suggest hypertensive women using hormonal contraceptives have higher cardiovascular risk. Estrogens may enhance blood coagulability by raising coagulation factors II, VII, VIII, IX, and X, fibrinogen, and soluble fibrin, while reducing antithrombin III and vascular wall fibrinolytic activator [7,8]. Hypertensive women need safe and effective contraceptive methods. Hormonal methods are very effective but may increase cardiovascular risk in high-risk women [8]. Evidence on the safety and effectiveness of all hormonal contraceptives is limited. Two critically low-quality systematic reviews [9,10] have evaluated the safety of only combined oral contraceptives (COCs) in hypertensive women. Current World Health Organization (WHO) recommendations [8] rely on individual studies and expert consensus rather than systematic reviews. This lack of high-quality evidence highlights the need for a systematic review of the safety and effectiveness of hormonal contraceptives in hypertensive women to guide clinical decisions. The characteristics of hormonal and non-hormonal methods are presented in S1–S2 Appendix.
This systematic review objective is to evaluate the safety and effectiveness of hormonal versus non-hormonal or non-use of contraception in women of reproductive age with a desire for future fertility and hypertension.
2. Methods
The protocol of this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO CRD42022324806). Results were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta Analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines [11–13] (S3–S5 Appendices). Likewise, this systematic review was carried out with the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions [14].
a. Eligibility criteria
There were no language or publication date restrictions. The intervention group comprised hormonal contraceptive users, while the comparator included non-hormonal or non-use of contraceptives.
Inclusion criteria: Studies assessing the safety (clinical trials (RCTs), cohorts, case-controls, case reports, case series, clinical trial records, and adverse event reports) or effectiveness (RCTs and cohorts) of hormonal contraception in hypertensive women of reproductive age (15–49 years) desiring future fertility.
Exclusion criteria: Studies exclusively comparing only hormonal contraceptives with each other, and those including women with polycystic ovary syndrome, abnormal uterine bleeding, heavy menstrual bleeding, or early ovarian failure (hormone replacement).
Reviews, meta-analyses, guidelines, expert consensus, abstracts, editorials, and comments were not considered for inclusion. Definitive surgical methods were not considered, as the focus was on women preserving fertility.
Outcomes considered were: Primary: MACE (death, AMI, CVD, hospitalization for unstable angina, need for coronary revascularization, hospitalization for acute heart failure or worsening of existing heart failure and TIA [5,6,15]) and unwanted pregnancies. Secondary: Pearl Index, pelvic inflammatory disease (PID), vaginal infections, infertility, contraception discontinuation due to side effects or drug interactions, worsening hypertension, peripheral arterial disease, venous thromboembolism (VTE), weight gain, and alteration in liver or kidney function.
b. Information sources and search strategies
The initial search (September 29–October 4, 2022) was updated on September 12–13, 2023, and August 7–8, 2024, in the databases Medline (via Ovid), Embase, Cochrane Central Registry of Controlled Trials (CENTRAL) and the database of Latin American and Caribbean Literature in Life Sciences Health (LILACS). Additionally, on June 27, 2022, August 26–27, 2023, and September 11–12, 2024, searches were carried out in the registries of clinical trials, regulatory agencies, and databases specialized in reporting adverse events, post-marketing safety and gray literature bases. A manual search of the references in the included studies was conducted to ensure all relevant studies were identified. The sources of information are in S6 Appendix, and the search strategies with updates are in S7 Appendix.
c. Study selection
After searching the databases, the records were uploaded into Rayyan [16] to remove duplicates. Then, two reviewers independently screened titles and abstracts, following the eligibility criteria. The selected studies were reviewed in full text by two reviewers independently. In case of discrepancies, a third reviewer was consulted. The reasons for not including studies that were read in full text are found in S8 Appendix. This process was also applied to gray literature, clinical experiment records, and safety reports on their respective platforms.
d. Data extraction and management
Information from the included full-text studies was extracted independently by two reviewers (NL, AB, MH, PG) on the REDCap platform [17]. Data extraction was performed independently. When differences occurred in the extracted data, they were resolved through dialogue and reviewing the evaluated study jointly. One reviewer transferred the collected data to Review Manager 5.4.1 [18]. In those cases in which specific data from the studies were not available, we sought to contact the authors of those studies. The items on the data extraction forms for each study design are found in S9 Appendix.
e. Evaluation of the risk of bias, methodological quality and critical approach of the included studies
Two reviewers (NL, AB, MH, PG) independently assessed the risk of bias in the cohort studies (ROBINS-I) [19], the methodological quality of the case-control studies (Newcastle-Ottawa) [20], and the critical approach of the included case series studies (Joanna Briggs Institute checklist) [21]. This information was compiled in REDCap [17]. Any disagreement was resolved through dialogue.
The certainty of evidence of each outcome was evaluated using the GRADE approach according to the type of study design [22].
f. Measures of the effect
For the dichotomous primary and secondary outcomes, we sought to use estimators adjusted for possible confounding variables that would present the relationship between the exposure and the outcome in hypertensive women. In the absence of these, Odds Ratios (OR) were calculated with their respective confidence intervals as measures of association. OR were estimated instead of RR since it is a more stable measure of association, and since the outcomes evaluated are rare in the population of interest, the OR does not overestimate the association. It was not possible to calculate OR adjusted for potential confounding variables, as we did not have the original data from the studies.
If the study did not report or a measure of association could not be calculated, narrative synthesis was performed. For continuous outcomes, narrative synthesis was performed because it was not possible to obtain from the studies the standard deviations or standard errors of the difference in means between the two groups that compared the studies, nor p value, t statistic, confidence intervals of the differences in intergroup averages.
g. Handling of unavailable data
In the presence of missing data, we tried to contact the authors of the studies to recover the information, however the response was not available.
h. Subgroup analysis and heterogeneity assessment
Subgroup analysis was conducted by type of hormonal contraceptive and by “current use” definition, considering prior use duration at the outcome index date in cases of considerable heterogeneity. Analysis by hypertension severity was planned but not performed due to lack of data.
Clinical, methodological, and statistical heterogeneity were assessed. Statistical heterogeneity was identified by evaluating confidence interval overlap and Chi² test p-values (<0.05, or <0.1 for small or few studies). Following the Cochrane Handbook, I² values were interpreted as: 0–29%: not important, 30–49%: moderate, 50–74%: substantial, and 75–100%: considerable heterogeneity [23].
i. Publication bias assessment
It was considered that if there were 10 or more studies, it would be evaluated using graphical methods (funnel plot) or statistical methods, when the number was less than 10 studies, we use the Tool for assessing Risk Of Bias due to Missing Evidence in a meta-analysis (ROB-ME) [24].
j. Data synthesis
Evidence was synthesized by hormonal contraceptive type and outcome, using quantitative methods (association estimators, vote counting, meta-analysis) and qualitative methods (narrative synthesis) when meta-analysis was not possible. Outcomes were presented by contraceptive type and study design.
Meta-analysis was conducted using Review Manager 5.4.1 [18], when at least two studies per outcome were available, with complete dichotomous outcome data, consistent effect measures, similar participants, exposure, and research questions, and no considerable heterogeneity. The approach considered clinical, methodological, and statistical diversity. When feasible, a random-effects meta-analysis using the DerSimonian and Laird method was performed to enhance generalizability, account for multiple exposure effects, and incorporate study heterogeneity [25].
For dichotomous outcomes in which meta-analysis was not performed, crude OR with their 95% confidence intervals (95%CI) were calculated using Stata 15 statistical software [26], and the OpenEpi software [27], if there was the information necessary for the calculation. For all outcomes in which meta-analysis could not be performed, synthesis was performed by vote counting based on the direction of effect [25]. Each effect estimate was classified as favoring the outcome, against the outcome, or showing no difference. Vote counting consisted of tallying the number of studies contributing to each direction of effect for a given outcome and was interpreted in conjunction with the certainty of the evidence. The continuous outcomes were synthesized qualitatively.
Summary tables were created using the GRADE approach to assess the certainty of evidence. Two reviewers (NL, AB) independently evaluated outcomes based on GRADE domains using GRADEpro GDT software [28]. The data synthesis structure is shown in the diagram in S10 Appendix.
k. Sensitivity analysis
For the sensitivity analysis, to evaluate the robustness of the conclusions, outcomes were compared by study design, considering risk of bias, methodological quality, or critical approach as appropriate.
l. Modifications to the protocol
- We added the category “current use” vs. “non-current use” of hormonal contraceptives as a new comparison based on data from case-control studies.
- Secondary outcomes were added: peripheral arterial disease and alteration of metabolic parameters.
- A new exposure category called “combined and progestin-only hormonal contraceptives” was created.
3. Results
a. Description of studies
A total of 32,225 records were identified from databases, clinical experiment databases, regulatory agencies, and gray literature (sources in S6 Appendix). From the databases (Medline, Embase, CENTRAL, LILACS), 26,454 records were identified. After removing 7,017 duplicates, 19,437 records were screened by title and abstract, selecting 65 for full-text review. Of these, 47 were not included [29–75] (reasons in S8 Appendix) getting 17 studies for analysis: 13 case-control [76–89], 2 were cohort [90,91] and 2 case series [92,93]. We did not find RCTs.
A total of 5,771 references were identified from clinical experiment databases, regulatory agencies, and gray literature, but none were included (Fig 1).
The study selection process and information sources are detailed in the PRISMA flowchart.
b. Studies characteristics
13 case-control studies were included [76–89], 2 cohort studies [90,91] and 2 case series [92,93]. The design of the studies, the types of hormonal contraceptives and their comparators, as well as the outcomes evaluated, are detailed in Table 1. The detailed characteristics of the studies included are in S11 Appendix, definitions of exposures and interventions are in S12 Appendix.
c. Assessment of the risk of bias, methodological quality and critical approach of the included studies
The 13 case-control studies [76–89] presented good methodological quality, the 2 cohort studies [90,91] presented a critical risk of bias and the 2 case series [92,93] presented low critical quality. In Tables 2–4 the evaluation of methodological quality, risk of bias and critical appraisal of these studies are presented. The details of these evaluations are presented in S11 Appendix. The evaluation of the certainty of the evidence of the outcomes for individual and grouped studies, using the GRADE approach, is found in S13–S14 Appendices.
d. Summary of the results
Outcomes by contraceptive method and study type are presented below. The certainty of evidence assessment is in S13–S14 Appendices and the 2 × 2 tables for OR calculations are in S15 Appendix. The very low certainty of the evidence in the outcomes was mainly due to the high risk of bias and issues of imprecision.
In case–control studies assessing safety outcomes, exposure was defined as “current use of a specific hormonal contraceptive”, and the comparator as “no current use of that specific hormonal contraceptive”. This comparator group included both previous and never users. The studies did not report whether participants were simultaneously using non-hormonal contraceptive methods; thus, the comparator group may have included women using non-hormonal methods or no contraception.
1. Combined hormonal contraceptives.
- a. Combined oral contraceptives
The evidence is very uncertain about the effect of COCs on avoiding unwanted pregnancies, ischemic CVD, AMI, VTE, worsening hypertension, weight gain, kidney function, and lipid alterations in hypertensive women; certainty of the evidence: very low. However, COCs may increase hemorrhagic CVD; certainty of evidence: low. Details of COCs outcomes identified through vote counting and narrative synthesis are in S16–S17 Appendices.
- 1. Unwanted pregnancies
One cohort study [90] assessed 56 hypertensive women (30 exposed to COCs, 26 unexposed), and found no pregnancies in either group.
- 2. Ischemic CVD
Three case-control studies [76,84,88] analyzed 613 hypertensive women: 299 cases (ischemic CVD; 73 exposed to COCs, 226 unexposed) and 314 controls (no ischemic CVD; 50 exposed, 264 unexposed). One study [84] suggests a possible positive association between COCs and ischemic CVD (crude OR= 3.95 (95% CI = 2.15–7.25), and the others two [76,88] suggest that there may be no difference (crude OR= 1.53 (95% CI = 0.75–3.11) and OR= 0.58 (95% CI = 0.21–1.64)). The certainty of the evidence is very low about the effect of COCs on ischemic CVD.
No meta-analysis was performed given the presence of considerable statistical heterogeneity (I2 = 81%, p value of chi2 = 0.005). Possible sources of heterogeneity in the population were sought: age, degree of arterial hypertension, presence of comorbidities, history of smoking, and management of the underlying pathology; in exposures: definition of exposure (current use), components and concentration of hormones in contraceptives, duration of use of hormonal contraceptives, use of other medications, perfect use compared to typical use of the hormonal contraceptive method and in the outcomes: the way the outcome was determined. It was only possible to perform a subgroup analysis based on the definition of exposure (current use) of contraceptives, since the studies did not describe the aforementioned characteristics in hypertensive women (Fig 2).
Test for subgroup differences: Chi2 = 5.66, df = 1 (P = 0.02), I2 = 82.3%.
The test for subgroup differences indicates a statistically significant effect (p = 0.02), suggesting that COC exposure time may modify its impact on ischemic CVD. However, substantial unexplained heterogeneity exists between the two case-control studies with the same COC exposure time (I² = 56%), making the validity of the effect estimation uncertain due to inconsistency in the studies evaluating this outcome.
- 3. Hemorrhagic CVD
Two case-control studies [84,85] analyzed 839 hypertensive women: 494 cases (hemorrhagic CVD; 79 exposed to COCs, 415 unexposed) and 345 controls (no hemorrhagic CVD; 39 exposed, 306 unexposed). Studies suggest COCs in hypertensive women may increase hemorrhagic CVD (pooled crude OR: 1.64 95% CI 1.08–2.50) (Fig 3). Certainty of evidence: low. The evaluation of publication bias is presented in S18 Appendix.
Outcome: hemorrhagic cerebrovascular event. Heterogeneity: Tau2 = 0.00; Chi2 = 0.00, df = 1 (P = 0.98); I2 = 0%.
- 4. AMI
A case-control study [82] and a case-series [92] assessed the presence of AMI and COCs use. The case-control study analyzed 175 hypertensive women: 114 cases (AMI; 27 exposed, 87 unexposed) and 61 controls (no AMI; 6 exposed, 55 unexposed). This study suggests a possible positive association between IAM and COCs (crude OR= 2.85 (95% CI: 1.10–8.93). The case series included 12 users of COCs with AMI, 3 of them were hypertensive. Certainty of the evidence: very low.
- 5. VTE
One case-control study [79] identified 69 cases with a first VTE event and 133 controls. Due to insufficient exposure data, the OR could not be calculated. Certainty of evidence: very low.
- 6. Worsening of baseline condition
A cohort study [90] evaluated systolic (SBP) and diastolic blood pressure (DBP) changes in 56 hypertensive women (30 exposed, 26 unexposed) and found no significant differences at six months between COC users and non-users. Users (n = 30)= mean SBP±Standard error(SE)= 127.8 ± 2.1 mmHg to 126.6 ± 2.5 mmHg, p = 0.57; mean DBP ± SE = 83.9 ± 1.3 mmHg to 83.7 ± 1.8 mmHg, p = 0.93. Non-users (n = 26)= SBP ± SE = 129.0 ± 2.5 mmHg to 130.3 ± 2.4 mmHg, p = 0.70; DBP ± SE = 87.6 ± 1.9 mmHg to 87.0 ± 1.4 mmHg, p = 0.57. Another cohort study [105] analyzed 65 hypertensive women (40 exposed, 25 unexposed) and found no changes in daytime SBP or nocturnal-daytime DBP at six months. However, nocturnal SBP decreased in COC users (114.5 ± 1.79 mmHg to 110.2 ± 1.77 mmHg, p = 0.032) but remained unchanged in non-users. Certainty of evidence: very low.
- 7. Increase of weight
Body Mass Index (BMI): Two cohort studies [90,91] assessed BMI in 121 hypertensive women (70 exposed, 51 unexposed). A study [90] reported a BMI decrease in COCs users after six months (mean BMI ± SE: initial = 30.3 ± 0.9 Kg/m² to 29.8 ± 0.9 Kg/m², p = 0.04), with no changes in non-users. The other study [91] found no BMI differences in either group after six months (users: mean BMI + -SE: initial = 28.9 + −0.78 Kg/m2 to 28.45 + −0.79 Kg/m2 (p = 0.620); non-users: initial = 30.79 + −1.20 Kg/m2 to 29.01 + −1.11 Kg/m2 (p = 0.27)). Certainty of evidence: very low.
Abdominal circumference: One cohort study [90] evaluated abdominal circumference in 56 hypertensive women and found no significant changes after six months (users: mean abdominal perimeter±SE = 97.9 ± 2.0 cm to 97.2 ± 2.0 cm, p = 0.66; non-users: 95.9 ± 2.6 cm to 94.8 ± 2.6 cm, p = 0.76). Certainty of evidence: very low.
- 8. Kidney function
One cohort study [90] found no significant differences in serum creatinine levels between COCs users and non-users after six months (users: mean creatinine±SE = 0.8 ± 0.0 mg/dL to 0.7 ± 0.0 mg/dL, p = 0.33; non-users = 0.8 ± 0.0 mg/dL to 0.7 ± 0.0 mg/dL, p = 0.41). Certainty of evidence: very low.
- 9. Lipid profile
Two cohort studies [90,91] evaluated lipid profile changes in a total of 121 hypertensive women (70 exposed, 51 unexposed) over six months. No significant differences were observed between COC users and non-users in total cholesterol, LDL cholesterol, HDL cholesterol, or triglyceride levels. Certainty of evidence: very low.
- b. Combined vaginal ring
The certainty of the evidence is very low about the effect of the vaginal ring on worsening hypertension, and lipid level alterations in hypertensive women; certainty of evidence: very low. A single case series [93] assessed these outcomes in 12 hypertensive women using the combined vaginal ring. S19–S20 Appendices present the narrative synthesis of quantitative outcomes for the vaginal ring.
- 1. Worsening of hypertension
No significant changes in SBP or DBP were observed over 12 months in women using the vaginal ring. Values remained stable across control, treatment, and recovery cycles (p value for DBP and SBP at each measurement time compared to cycle 0: not significant (the significance value is not reported)).
- 2. Lipids
For 12 months of observation of the women with the vaginal ring, a decrease in total cholesterol was observed (mean±Standard deviation(SD): 182 ± 30 mg/100mL to 157 ± 26 mg/100mL, p < 0.01), driven by a reduction in HDL cholesterol (59 ± 10 mg/100mL to 38 ± 3 mg/100mL, p < 0.001), with no significant changes in LDL cholesterol. Triglycerides also decreased (52 ± 17 mg/100mL to 38 ± 11 mg/100mL, p < 0.05).
- c. Combined injectable contraceptives
The evidence is very uncertain about the effect of combined injectable contraceptives on CVD, AMI, and VTE in hypertensive women; certainty of evidence: very low. A case-control study [80] assessed these outcomes. S21 Appendix presents the synthesis of results for combined injectable contraceptives using the vote-counting method.
- 1. Hemorrhagic and ischemic CVD
The study analyzed 942 hypertensive women: 573 cases (CVD; 2 exposed, 571 unexposed) and 369 controls (no CVD; 1 exposed, 368 unexposed) (crude OR= 1.29 (IC 95% 0.07–76.24)).
- 2. AMI
The study analyzed 138 hypertensive women: 85 cases (AMI; 1 exposed, 84 unexposed) and 53 controls (no AMI; 0 exposed, 53 unexposed) (crude OR = 1.26; 95% CI: 0.04–38.27).
- 3. VTE
The analyzed 132 hypertensive women: 41 cases (VTE; 0 exposed, 41 unexposed) and 91 controls (no VTE; 0 exposed, 91 unexposed).
2. Progestin-only contraceptives.
- a. Progestin-only pill
There is very low certainty in the evidence about the effect of progestin-only pill (POPs) on CVD, AMI, and VTE in hypertensive women; certainty of evidence: very low. A case-control study [80], assessed these outcomes for this contraceptive. S22 Appendix presents the synthesis of results for POPs using the vote-counting method.
- 1. Hemorrhagic and ischemic CVD
This study included 960 hypertensive women (585 cases (14 exposed to POPs, 571 non-exposed), 375 controls (7 exposed to POPs, 368 non-exposed)). The study suggested that POPs may reduce, increase or have little to no effect on CVD in hypertensive women (crude OR= 1.29 (IC 95% 0.48–3.81)), but the evidence is very uncertain.
- 2. AMI
For AMI, they included 139 hypertensive women (85 cases (1 exposed to POPs, 84 non-exposed), 54 controls (1 exposed to POPs, 53 non-exposed)). The study suggested that POPs may reduce, increase or have little to no effect on AMI in hypertensive women (crude OR= 0.63 (IC 95% 0.01–50)), but the certainty of the evidence is very low.
- 3. VTE
The study included 135 hypertensive women: 42 cases (VTE; 1 exposed, 41 unexposed) and 93 controls (no VTE; 2 exposed, 91 unexposed). The study suggested that POPs may reduce, increase or have little to no effect on VTE in hypertensive women (crude OR=1.11 (IC 95% 0.02–21.86)), but the evidence is very uncertain.
- b. Progestin-only injectable
The certainty of the evidence is very low about the effect of progestin-only injectable on CVD, AMI, and VTE in hypertensive women; certainty of evidence: very low. A case-control study [80], assessed these outcomes for this contraceptive. S23 Appendix presents the details of the outcomes identified using the vote-counting method for progestin-only injectables.
- 1. Hemorrhagic and ischemic CVD
The study included 944 hypertensive women: 576 cases (CVD; 5 exposed, 571 unexposed) and 368 controls (no CVD; 0 exposed, 368 unexposed). The study suggested that progestin-only injectables may reduce, increase or have little to no effect on CVD in hypertensive women (crude OR= 6.45 (IC 95% 0.35–118.3)), but the evidence is very uncertain.
- 2. AMI
The study included 137 hypertensive women: 84 cases (AMI; 0 exposed, 84 unexposed) and 53 controls (no AMI; 0 exposed, 53 unexposed). Progestin-only injectables may reduce, increase or have little to no effect on AMI, but there is very low certainty in the evidence.
- 3. VTE
The study included 133 hypertensive women: 41 cases (VTE; 0 exposed, 41 unexposed) and 92 controls (no VTE; 1 exposed, 91 unexposed). The study suggested that progestin-only injectables may reduce, increase or have little to no effect on hemorrhagic or ischemic CVD in hypertensive women (crude OR= 1.11 (IC95% 0.04–33.74)), but the evidence is very uncertain.
3. Combined hormonal and progestin-only contraceptives.
The certainty of the evidence is very low about the effect of COCs and POPs on ischemic or hemorrhagic CVD, AMI and peripheral arterial disease in hypertensive women; certainty of evidence: very low. The synthesis of the results using the voting count method is presented in S24 Appendix.
- a. Ischemic CVD
Two case-control studies [86,87,89], evaluated the presence of ischemic CVD among hypertensive women users of COC or POP. No meta-analysis was performed given the presence of considerable statistical heterogeneity (I2 = 80%, p value of the chi2 = 0.03). Only a subgroup analysis could be performed based on the definition of exposure (current use) of contraceptives used by women in the studies (Fig 4).
Test for subgroup differences: Chi2 = 4.92, df = 1 (P = 0.03), I2 = 79.7%.
The test of subgroup differences suggests there is a statistically significant subgroup effect (p = 0.03). This suggests the exposure time of COCs or POPs could modify their effect in the presence of ischemic CVD. The evidence is very uncertain on the effect of COCs or POPs on ischemic CVD in hypertensive women.
- b. Hemorrhagic and ischemic CVD
A case-control study [78] included 117 hypertensive women: 51 cases (CVD; 21 exposed, 30 unexposed) and 66 controls (no CVD; 23 exposed, 43 unexposed). This study suggests that the use of COCs or POPs may reduce, increase or have little to no effect on CVD in hypertensive women (crude OR= 1.31 (95% CI 0.62–2.78)), but the certainty of the evidence is very low.
- c. AMI
Two case-control studies [77,83] assessed AMI in hypertensive women, comparing cases (AMI) and controls (no AMI) based on COC or POP use. The evidence is very uncertain about the effect of COC or POP on AMI in hypertensive women (crude OR= 1.15 (95% CI 0.60–2.19)). Certainty of the evidence: very low (Fig 5). The evaluation of publication bias is presented in S25 Appendix.
Outcome: acute myocardial infarction. Heterogeneity: Tau2 = 0.00; Chi2 = 0.35, df = 1 (P = 0.55); I2 = 0%.
- d. Peripheral arterial disease
A case-control study [81] analyzed 98 hypertensive women: 43 cases (peripheral arterial disease; 16 exposed, 27 unexposed) and 55 controls (no peripheral arterial disease; 19 exposed, 36 unexposed). The study suggested that COCs or POPs may reduce, increase or have little to no effect on peripheral arterial disease in hypertensive women (crude OR= 1.12 (95% CI 0.45–2.79)), but the evidence is very uncertain.
The presentation summary of this article is in S26 Appendix. Articles screened by title and abstract from the databases can be found in S27 Appendix.
4. Discussion
a. Findings and interpretation
Evidence suggests that COCs may increase hemorrhagic CVD in hypertensive women, although the certainty of the evidence is low. The evidence is very uncertain regarding the effect of COCs on pregnancy prevention, ischemic CVD, AMI, venous thromboembolism, worsening hypertension, weight gain, kidney function, and lipid profile alterations in hypertensive women. The effect of COCs or POPs on CVD, AMI, and peripheral arterial disease is also very uncertain, as is the effect of POPs, progestin-only injectables, or combined injectable contraceptives on CVD, AMI, and venous thromboembolism, and the combined vaginal ring on worsening hypertension, and lipid profile alteration. The very low certainty of the evidence was mainly due to a high risk of bias and issues of imprecision. For outcomes with considerable heterogeneity, it was not possible to identify its sources.
We found no studies assessing the safety or effectiveness of the patch, implants, emergency contraceptives, or levonorgestrel-releasing intrauterine devices (LNG-IUDs) in hypertensive women. PID, vaginal infections, fertility loss, liver function alterations, and the Pearl Index were not found.
b. Results in the context of what is known
WHO recommendations on the use of COCs in hypertensive women [8], are based on primary studies, systematic reviews not specifically focused on hypertensive women [94,95] and expert consensus. The individual studies are found in two reviews (critically low quality (AMSTAR-2)) from 2002 and 2006 assessing COC safety in hypertensive women [9,10], concluding that COC users have a higher risk of CVD and AMI compared to non-users, with no increase in venous thromboembolism. Differences with our results may relate to the certainty assessments, precision evaluation based on optimal data sizes (unclear in those reviews), and exclusion of ineligible studies [29,62–69,96].
WHO lacks supporting evidence for the combined patch, vaginal ring, and combined injectables, but classifies all combined hormonal contraceptives as category 3–4 in the Medical Eligibility Criteria for Contraceptive Use (MEC), indicating risks generally outweigh benefits [8]. We identified one case series on the vaginal ring [93] and one case-control study on combined injectables [80], both providing very low certainty of the evidence for the outcomes evaluated.
WHO recommendations [8] for progestogen-only contraceptives rely on a single study [80], the only one found for POPs and injectables. Similarly, recommendations for implants, emergency contraceptives, and LNG-IUDs lack supporting studies, consistent with our findings. WHO classifies progestogen-only contraceptives as category 1–3 in the MEC, indicating no restriction or that risks outweigh benefits [8]. In our review, the certainty of evidence for the outcomes was very low. The characteristics and mechanisms of action of hormonal contraceptives are provided in S1 Appendix [97–102].
c. Clinical implications
Evidence suggests that COCs in hypertensive women may increase hemorrhagic CVD, but the certainty is low. For other outcomes, the certainty is very low; therefore, the safety and effectiveness of COCs, the vaginal ring, combined injectables, and progestin-only methods in hypertensive women cannot be conclusively established.
d. Research implications
The ideal study to assess the safety and effectiveness of hormonal contraception in hypertensive women is a pragmatic clinical trial. Cohort studies using administrative data and causal inference analyses also represent viable alternatives. Upcoming research should be methodologically rigorous, with adequate statistical power and strategies to reduce bias.
e. Strengths and Limitations
Our review comprehensively searched for studies on hormonal contraceptives in hypertensive women, including various study designs. Unlike previous reviews focused only on COCs, we evaluated all hormonal contraceptive methods. Risk of bias and study quality were assessed using tools specific to each design [19–21], and we applied GRADE to evaluate certainty of evidence. We synthesized data qualitatively and quantitatively. All processes were documented in a protocol registered in PROSPERO [22].
Limitations include the inability to evaluate hypertension severity and contraceptive safety due to insufficient classification in the studies. All outcomes had very low certainty of evidence, except for the possible association between COCs and hemorrhagic CVD (low evidence). There are no adequate tools to assess bias in case-control studies or case series. Information on comorbidities, cardiovascular risk factors, duration of contraceptive exposure, and ages of hypertensive women using hormonal contraceptives was unavailable in the studies.
No studies evaluated outcomes for the patch, levonorgestrel and etonogestrel implants, emergency contraceptives, or LNG-IUDs.
5. Conclusions
This systematic review suggests that COCs may increase hemorrhagic CVD in hypertensive women, although the certainty of the evidence is low. For all other outcomes evaluated, including those related to COCs, vaginal ring, combined injectables, and progestin-only methods, the certainty of the evidence was very low. The safety and effectiveness of hormonal contraceptive methods in hypertensive women of reproductive age remain uncertain.
There is a need for high-quality primary studies in this population. Future research should aim to reduce bias, include adequately powered sample sizes, and clearly define study populations. Given the substantial uncertainty, existing clinical recommendations should be maintained, with particular caution regarding the use of COCs due to their possible association with hemorrhagic CVD.
Supporting information
S1 Appendix. Classification of hormonal contraceptive methods, percentages of unwanted pregnancies with perfect and typical use during the first year and side effects and side effects.
https://doi.org/10.1371/journal.pone.0345959.s001
(PDF)
S2 Appendix. Classification of non-hormonal contraceptive methods, percentage of unwanted pregnancies in the first year according to the hormonal contraceptive method with perfect and typical use.
https://doi.org/10.1371/journal.pone.0345959.s002
(PDF)
S4 Appendix. PRISMA 2020 for abstracts checklist.
https://doi.org/10.1371/journal.pone.0345959.s004
(PDF)
S5 Appendix. MOOSE checklist for meta-analyses of observational studies.
https://doi.org/10.1371/journal.pone.0345959.s005
(PDF)
S8 Appendix. Characteristics of studies not included.
https://doi.org/10.1371/journal.pone.0345959.s008
(PDF)
S9 Appendix. Data extraction format for studies on hormonal contraceptives and hypertensive women.
https://doi.org/10.1371/journal.pone.0345959.s009
(PDF)
S11 Appendix. Detailed characteristics of the included studies and assessment of risk of bias, methodological quality and critical approach.
https://doi.org/10.1371/journal.pone.0345959.s011
(PDF)
S12 Appendix. General characteristics of the exposures/interventions and study comparators.
https://doi.org/10.1371/journal.pone.0345959.s012
(PDF)
S13 Appendix. Summary table of results of included GRADE studies.
https://doi.org/10.1371/journal.pone.0345959.s013
(PDF)
S14 Appendix. Evidence quality assessment table for individual studies.
https://doi.org/10.1371/journal.pone.0345959.s014
(PDF)
S15 Appendix. 2x2 tables of the included case-control studies.
https://doi.org/10.1371/journal.pone.0345959.s015
(PDF)
S16 Appendix. Synthesis of outcomes related to the use of combined oral contraceptives using the vote counting method.
https://doi.org/10.1371/journal.pone.0345959.s016
(PDF)
S17 Appendix. Narrative synthesis of continuous outcomes for combined oral contraceptives.
https://doi.org/10.1371/journal.pone.0345959.s017
(PDF)
S18 Appendix. ROB-ME Current use of combined oral contraceptives compared with no current use (past use or never used) of combined oral contraceptives in hypertensive women.
Outcome: hemorrhagic cerebrovascular event.
https://doi.org/10.1371/journal.pone.0345959.s018
(PDF)
S19 Appendix. Synthesis of results related to the use of the combined contraceptive vaginal ring using the vote counting method.
https://doi.org/10.1371/journal.pone.0345959.s019
(PDF)
S20 Appendix. Narrative synthesis of continuous outcomes for vaginal ring.
https://doi.org/10.1371/journal.pone.0345959.s020
(PDF)
S21 Appendix. Synthesis of the results related to the use of the combined injectable contraceptive using vote-counting method.
https://doi.org/10.1371/journal.pone.0345959.s021
(PDF)
S22 Appendix. Synthesis of results related to the use of progestin-only pills using the vote counting method.
https://doi.org/10.1371/journal.pone.0345959.s022
(PDF)
S23 Appendix. Synthesis of results related to the use of progestin-only injectables using the vote counting method.
https://doi.org/10.1371/journal.pone.0345959.s023
(PDF)
S24 Appendix. Synthesis of results related to the use of combined oral contraceptives or progestin-only pills using the vote counting method.
https://doi.org/10.1371/journal.pone.0345959.s024
(PDF)
S25 Appendix. ROB-ME Current use of combined oral contraceptives or progestin-only pills compared with no current use (past use or never used) of combined oral contraceptives or progestin-only pills in hypertensive women.
Outcome: acute myocardial infarction.
https://doi.org/10.1371/journal.pone.0345959.s025
(PDF)
S27 Appendix. Articles screened by title and abstract from the databases.
https://doi.org/10.1371/journal.pone.0345959.s027
(PDF)
Acknowledgments
Thanks to the Universidad Nacional de Colombia for allowing the academic growth of its students, as well as the development of this study.
References
- 1. GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1459–544. pmid:27733281
- 2. Organización para la Cooperación y el Desarrollo Económicos. Age of mothers at childbirth and age-specific fertility. OECD [Internet]. 2021. Available from:
- 3. Organisation for economic co-operation and development. OECD.Stat. Organisation for economic co-operation and development: Family Database. [cited 2023 Oct 7]. Available from: https://stats.oecd.org/Index.aspx?DataSetCode=FAMILY
- 4. International Federation of Gynecology and Obstetrics (FIGO). Pregnancy: Risks and Complications, Figo [Internet]. 2021 [cited 2021 Dec 28]. Available from: https://www.figo.org/pregnancy-risks-and-complications
- 5. Medicines Agency E. Reflection paper on assessment of cardiovascular safety profile of medicinal products. Comm Med Prod Hum Use CHMP [Internet]. 2016; Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-assessment-cardiovascular-safety-profile-medicinal-products_en.pdf
- 6. Food and Drug Administration (FDA). FDA Background Document Endocrinologic and Metabolic Drugs Advisory Committee Meeting. FDA [Internet]. 2018; Available from: https://www.fda.gov/media/121272/download
- 7. Beller FK, Ebert C. Effects of oral contraceptives on blood coagulation. A review. Obstet Gynecol Surv. 1985;40(7):425–36. pmid:3895067
- 8.
World Health Organization. Medical eligibility criteria for contraceptive use. 5th ed. WHO Library Cataloguing-in-Publication Data, editor. Geneva: World Health Organization; 2015. pp. 1–276.
- 9. Curtis KM, Chrisman CE, Peterson HB, WHO Programme for Mapping Best Practices in Reproductive Health. Contraception for women in selected circumstances. Obstet Gynecol. 2002;99(6):1100–12.
- 10. Curtis KM, Mohllajee AP, Martins SL, Peterson HB. Combined oral contraceptive use among women with hypertension: a systematic review. Contraception. 2006;73(2):179–88. pmid:16413848
- 11. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. pmid:19621072
- 12. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
- 13. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12.
- 14. Cochrane Handbook for Systematic Reviews of Interventions version 6.5 (updated August 2024). 2024 [cited 2024 Oct 10]. Available from: https://training.cochrane.org/handbook
- 15. Bosco E, Hsueh L, McConeghy KW, Gravenstein S, Saade E. Major adverse cardiovascular event definitions used in observational analysis of administrative databases: a systematic review. BMC Med Res Methodol. 2021;21(1):241. pmid:34742250
- 16. Mourad O, Hossam H, Zbys F, Ahmed E. Rayyan: a web and mobile app for systematic reviews. Syst Rev. 2016.
- 17. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, et al. The REDCap consortium: Building an international community of software platform partners. J Biomed Inform. 2019;95:103208. pmid:31078660
- 18. Collaboration TC. Review Manager (RevMan) [Internet]. 2020. Available from: https://training.cochrane.org/online-learning/core-software-cochrane-reviews/revman/revman-5-download/download-and-installation
- 19. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919. pmid:27733354
- 20. Wells G, Shea B, O’Connell D, Peterson J, Welch V. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analysis [Internet]. The Ottawa Hospital. 2011 [cited 2022 Mar 15]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
- 21. Munn Z, Barker TH, Moola S, Tufanaru C, Stern C, McArthur A, et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synth. 2020;18(10):2127–33. pmid:33038125
- 22. Schünemann H, Brozek J, Guyatt G, Oxman A. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) [Internet]. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group. GRADE; 2013. Available from: https://gdt.gradepro.org/app/handbook/handbook.html
- 23.
Deeks JJ, Higgins JPT, Altman DG. Analysing data and undertaking meta-analyses. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane Handbook for Systematic Reviews of Interventions. 6.2 ed. Cochrane; 2021.
- 24. Page M, Sterne J, Boutron I, Hróbjartsson A, Kirkham J, Li T, et al. ROB-ME: a tool for assessing risk of bias due to missing evidence in systematic reviews with meta-analysis. BMJ. 2023.
- 25.
McKenzie JE, Brennan SE, Ryan RE, Thomson HJ, Johnston RV. Chapter 9: Summarizing study characteristics and preparing for synthesis. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane Handbook for Systematic Reviews of Interventions version. 6.2 ed. Cochrane; 2021. Available from: https://training.cochrane.org/handbook/current/chapter-09
- 26. Stata. Stata 15 [Internet]. Stata. 2017 [cited 2022 Mar 15]. Available from: https://www.stata.com/stata15/
- 27. Kevin MS, Andrew GD. EpiInformatics.com. OpenEpi: Open Source Epidemiologic Statistics for Public Health. [cited 2023 Oct 17]. Available from: https://www.openepi.com/TwobyTwo/TwobyTwo.htm
- 28.
University M. GRADEpro GDT [Internet]. Hamilton (ON): McMaster University (developed by Evidence Prime). Available from: gradepro.org
- 29. Lewis MA, Heinemann LA, Spitzer WO, MacRae KD, Bruppacher R. The use of oral contraceptives and the occurrence of acute myocardial infarction in young women. Results from the Transnational Study on Oral Contraceptives and the Health of Young Women. Contraception. 1997;56(3):129–40. pmid:9347202
- 30. Dinger J, Assmann A, Möhner S, Minh TD. Risk of venous thromboembolism and the use of dienogest- and drospirenone-containing oral contraceptives: results from a German case-control study. J Fam Plann Reprod Health Care. 2010;36(3):123–9. pmid:20659364
- 31. Adler TE, Usselman CW, Takamata A, Stachenfeld NS. Blood pressure predicts endothelial function and the effects of ethinyl estradiol exposure in young women. Am J Physiol Heart Circ Physiol. 2018;315(4):H925–33. pmid:29906227
- 32. Ananijević-Pandey J, Vlajinac H. Myocardial infarction in young women with reference to oral contraceptive use. Int J Epidemiol. 1989;18(3):585–8. pmid:2807660
- 33. Andrews J. ACP Journal Club. Hormonal contraceptives with ethinyl estradiol were associated with increased thrombotic stroke and MI. Ann Intern Med. 2012;157(8):JC4–9. pmid:23070511
- 34. Correia P, Machado S, Eskandari A, Michel P. Ischemic stroke in women using contraceptives: causes, characteristics and outcome. Int J Stroke. 2016;11(3_suppl):4–288.
- 35. Dinger J, Assmann A, Moehner S. Long-term active surveillance study for oral contraceptives (LASS): impact of oral contraceptive use on the start of antihypertensive treatment. Pharmacoepidemiol Drug Saf. 2010;19:S232.
- 36. Alcalde Dominguez A, Rabasa Antonijuan J, Cusidó Gimferrer M, Ortuño MJ. Therapy with ulipristal acetate in a hypertensive patient. Case Rep Med. 2018;2018:1091520. pmid:30515219
- 37. Dong W, Colhoun HM, Poulter NR. Blood pressure in women using oral contraceptives: results from the Health Survey for England 1994. J Hypertens. 1997;15(10):1063–8. pmid:9350579
- 38. Dunn NR, Arscott A, Thorogood M. The relationship between use of oral contraceptives and myocardial infarction in young women with fatal outcome, compared to those who survive: results from the MICA case-control study. Contraception. 2001;63(2):65–9. pmid:11292469
- 39. Fisch IR, Frank J. Oral contraceptives and blood pressure. JAMA. 1977;237(23):2499–503.
- 40. Mekonnen TT, Woldeyohannes SM, Yigzaw T. Contraceptive use in women with hypertension and diabetes: cross-sectional study in northwest Ethiopia. Int J Womens Health. 2015;7:957–64. pmid:26715862
- 41. Millet D, Keledjian P, Corvol P. Contraception par la norgestrienone en continu chez les femmes hypertendues. Effets sur la tension arterielle, les lipides, la glycemie et l’angiotensinogene [Internet]. [cited 2023 May 28]. Available from: https://www.embase.com/records?subaction=viewrecord&id=L10153096
- 42. Kalenga CZ, Metcalfe A, Ahmed SB, Sharanya R, MacRae JM, Nerenberg K. Association between non-oral hormonal contraceptives and blood pressure: a systematic review. Hypertension. 2019;74(Suppl_1):A031–A031.
- 43. Kalenga CZ, Dumanski SM, Metcalfe A, Robert M, Nerenberg KA, MacRae JM, et al. The effect of non-oral hormonal contraceptives on hypertension and blood pressure: a systematic review and meta-analysis. Physiol Rep. 2022;10(9):e15267. pmid:35510324
- 44. Kovell LC, Meyerovitz CV, Skaritanov E, Ayturk D, Person SD, Kumaraswami T. Hypertension and contraceptive use among women of child-bearing age in the United States from 2001 to 2018. J Hypertens. 2022;40(4):776–84.
- 45. Leaf DA, Bland D, Schaad D, Neighbor WE, Scott CS. Oral contraceptive use and coronary risk factors in women. Am J Med Sci. 1991;301(6):365–8. pmid:2039021
- 46. Lidegaard O, Edström B, Kreiner S. Oral contraceptives and venous thromboembolism. a case-control study. Contraception. 1998;57(5):291–301. pmid:9673836
- 47. Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ. 2011;343:d6423.
- 48. Mann J, Vessey M, Thorogood M, Doll S. Myocardial infarction in young women with special reference to oral contraceptive practice [Internet]. 1975 [cited 2023 Oct 14]. Available from: https://pubmed.ncbi.nlm.nih.gov/1169093/
- 49. Meinel H, Göretzlehner G, Heinemann L. Hormonal contraceptives and cardiovascular risk. Results of an East German multicenter case control study. Zentralbl Gynakol. 1988;110(23):1507–14. pmid:3071053
- 50. Nessa A, Latif SA, Siddiqui NI. Risk of cardiovascular diseases with oral contraceptives. Mymensingh Med J. 2006;15(2):220–4. pmid:16878110
- 51. Perritt J, Fox M, Jamshidi R, Wang J, McDonald-Mosley R, Burke AE. Undesired pregnancy, contraceptive counseling and postpartum contraception use in women with medical comorbidities: an analysis of data from the Maryland Pregnancy Risk Assessment Monitoring System. Contraception. 2011;84(3):325–6.
- 52. Wieder DR, Pattimakiel L. Examining the efficacy, safety, and patient acceptability of the combined contraceptive vaginal ring (NuvaRing). Int J Womens Health. 2010;2:401–9. pmid:21151688
- 53. Arthes FG, Masi AT. Myocardial infarction in younger women. Associated clinical features and relationship to use of oral contraceptive drugs. Chest. 1976;70(5):574–83. pmid:975971
- 54. Chaudhury N, Gupta AN, Hazra MN, Hingorani V, Kochhar M, Kodkany BS. Phase III-clinical trial with Norplant-2 (covered rods). Report of a 24-month study. Contraception. 1988;38(6):659–73.
- 55. Chen BA, Panther L, Marzinke MA, Hendrix CW, Hoesley CJ, van der Straten A, et al. Phase 1 safety, pharmacokinetics, and pharmacodynamics of dapivirine and maraviroc vaginal rings: a double-blind randomized trial. J Acquir Immune Defic Syndr. 2015;70(3):242–9. pmid:26034880
- 56. Maino A, Siegerink B, Algra A, Peyvandi F, Rosendaal FR. Recurrence and mortality in young women with myocardial infarction or ischemic stroke: long-term follow-up of the risk of arterial thrombosis in relation to oral contraceptives (RATIO) Study. JAMA Intern Med. 2016;176(1):134–6. pmid:26595612
- 57. Sivin I, Stern J. Health during prolonged use of levonorgestrel 20 micrograms/d and the copper TCu 380Ag intrauterine contraceptive devices: a multicenter study. Fertil Steril. 1994;61(1):70–7.
- 58. Ueda Y, Kamiya CA, Horiuchi C, Miyoshi T, Hazama R, Tsuritani M, et al. Safety and efficacy of a 52-mg levonorgestrel-releasing intrauterine system in women with cardiovascular disease. J Obstet Gynaecol Res. 2019;45(2):382–8. pmid:30259601
- 59. Wang C, Li Y, Bai J, Qian W, Zhou J, Sun Z, et al. General and central obesity, combined oral contraceptive use and hypertension in Chinese women. Am J Hypertens. 2011;24(12):1324–30. pmid:21881619
- 60. Mant J, Painter R, Vessey M. Risk of myocardial infarction, angina and stroke in users of oral contraceptives: an updated analysis of a cohort study. Br J Obstet Gynaecol. 1998;105(8):890–6. pmid:9746383
- 61. Jensen G, Nyboe J, Appleyard M, Schnohr P. Risk factors for acute myocardial infarction in Copenhagen, II: Smoking, alcohol intake, physical activity, obesity, oral contraception, diabetes, lipids, and blood pressure. Eur Heart J. 1991;12(3):298–308. pmid:2040311
- 62. Dunn N, Thorogood M, Faragher B, de Caestecker L, MacDonald TM, McCollum C. Oral contraceptives and myocardial infarction: results of the MICA case-control study. BMJ. 1999;318(7198):1579–84.
- 63. D’Avanzo B, La Vecchia C, Negri E, Parazzini F, Franceschi S. Oral contraceptive use and risk of myocardial infarction: an Italian case-control study. J Epidemiol Community Health. 1994;48(3):324–5. pmid:8051537
- 64. Lidegaard O. Oral contraceptives, pregnancy and the risk of cerebral thromboembolism: the influence of diabetes, hypertension, migraine and previous thrombotic disease. Br J Obstet Gynaecol. 1995;102(2):153–9. pmid:7756208
- 65. Lidegaard Ø, Kreiner S. Contraceptives and cerebral thrombosis: a five-year national case-control study. Contraception. 2002;65(3):197–205. pmid:11929641
- 66. Siritho S, Thrift AG, McNeil JJ, You RX, Davis SM, Donnan GA, et al. Risk of ischemic stroke among users of the oral contraceptive pill: The Melbourne Risk Factor Study (MERFS) Group. Stroke. 2003;34(7):1575–80.
- 67. Nightingale A, Farmer RDT. Ischemic stroke in young women: a nested case-control study using the UK General Practice Research Database - PubMed [Internet]. 2004 [cited 2023 May 28]. Available from: https://pubmed.ncbi.nlm.nih.gov/15143296/
- 68. Narkiewicz K, Graniero GR, D’Este D, Mattarei M, Zonzin P, Palatini P. Ambulatory blood pressure in mild hypertensive women taking oral contraceptives. A case-control study. Am J Hypertens. 1995;8(3):249–53. pmid:7794573
- 69. Lubianca JN, Faccin CS, Fuchs FD. Oral contraceptives: a risk factor for uncontrolled blood pressure among hypertensive women. Contraception. 2003;67(1):19–24. pmid:12521653
- 70. Ojelabi I. Biochemical and clinical effects of contraceptives among women of reproductive age in southwest, Nigeria. Clin Chim Acta. 2024;558:119052.
- 71. Costescu D, Creinin MD, Douxfils J, Foidart JM, Gaspard U, Danielsson KG. The Impact of the Combined Oral Contraceptive Estetrol 15 mg/Drospirenone 3 mg (E4/DRSP) on Blood Pressure: Pooled Data from Two Phase III Clinical Trials. J Obstet Gynaecol Can. 2024;46(5):102482.
- 72. Spielvogel R, Stephens RB, Clark R, Guillen M, Hankins A, Parise C. Providing family planning counseling services for women with chronic medical conditions in an inpatient setting: A randomized feasibility trial. Contraception. 2023;128:110133. pmid:37549724
- 73. Neill S, Farrell A, Roselle A, Schneider L, Dodge L, Dutton C, et al. Contraceptive chosen among patients with elevated cardiovascular and thromboembolism risk profile. Contraception. 2023;127:110246.
- 74. Jeong SM, Jeon KH, Jung W, Yoo JE, Yoo J, Han K, et al. Association of reproductive factors with cardiovascular disease risk in pre-menopausal women: nationwide population-based cohort study. Eur J Prev Cardiol. 2023;30(3):264–73.
- 75. Abdrebbi SB. Contraception in women with cardiovascular risk. J Hypertens. 2024;42(Suppl 1):e322.
- 76. Heinemann LA, Lewis MA, Spitzer WO, Thorogood M, Guggenmoos-Holzmann I, Bruppacher R. Thromboembolic stroke in young women. A European case-control study on oral contraceptives. Contraception. 1998;57(1):29–37.
- 77. Croft P, Hannaford PC. Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners’ oral contraception study. BMJ. 1989;298(6667):165–8.
- 78. Hannaford PC, Croft PR, Kay CR. Oral contraception and stroke. Evidence from the Royal College of General Practitioners’ Oral Contraception Study. Stroke. 1994;25(5):935–42. pmid:8165687
- 79. World Health Organization. Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. The Lancet. 1995;346(8990):1575–82.
- 80. World Health Organization. Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case-control study. Contraception. 1998;57(5):315–24.
- 81. Van Den Bosch MAAJ, Kemmeren JM, Tanis BC, Mali WPTM, Helmerhorst FM, Rosendaal FR. The RATIO study: oral contraceptives and the risk of peripheral arterial disease in young women. J Thromb Haemost. 2003;1(3):439–44.
- 82. Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. The Lancet. 1997;349(9060):1202–9.
- 83. Tanis BC, van den Bosch MA, Kemmeren JM, Cats VM, Helmerhorst FM, Algra A. Oral contraceptives and the risk of myocardial infarction. N Engl J Med. 2001;345(25):1787–93.
- 84. Collaborative Group for the Study of Stroke in Young Women. Oral contraceptives and stroke in young women: associated risk factors. JAMA. 1975;231(7):718–22.
- 85. World Health Organization. Haemorrhagic stroke, overall stroke risk, and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet. 1996;348(9026):505–10.
- 86. Lidegaard O. Oral contraception and risk of a cerebral thromboembolic attack: results of a case-control study. BMJ. 1993;306(6883):956–63.
- 87. Lidegaard O. Oral contraceptives, pregnancy and the risk of cerebral thromboembolism: the influence of diabetes, hypertension, migraine and previous thrombotic disease. Br J Obstet Gynaecol. 1995;102(2):153–9. pmid:7756208
- 88. World Health Organization. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet. 1996;348(9026):498–505.
- 89. Kemmeren JM, Tanis BC, van den Bosch MAAJ, Bollen ELEM, Helmerhorst FM, van der Graaf Y, et al. Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) study: oral contraceptives and the risk of ischemic stroke. Stroke. 2002;33(5):1202–8. pmid:11988591
- 90. de Morais TL, Giribela C, Nisenbaum MG, Guerra G, Mello N, Baracat E, et al. Effects of a contraceptive containing drospirenone and ethinylestradiol on blood pressure, metabolic profile and neurohumoral axis in hypertensive women at reproductive age. Eur J Obstet Gynecol Reprod Biol. 2014;182:113–7. pmid:25268778
- 91. de Rossi P, Giribela CRG, Baracat EC, Colombo FMC, Melo NR. Evaluation of blood pressure, body mass index, lipid profile and insulin resistance in mild hypertensive overweight women with the use of a low dose combined oral contraceptive containing drospirenone: Results from a prospective clinical trial. G Ital Ostet E Ginecol. 2014;36:117–9.
- 92. Bounhoure J-P, Galinier M, Roncalli J, Assoun B, Puel J. Myocardial infarction and oral contraceptives. Bull Acad Natl Med. 2008;192(3):569–79; discussion 579. pmid:18819701
- 93. Elkik F, Basdevant A, Jackanicz TM, Guy-Grand B, Mercier-Bodard C, Conard J, et al. Contraception in hypertensive women using a vaginal ring delivering estradiol and levonorgestrel. J Clin Endocrinol Metab. 1986;63(1):29–35. pmid:3086360
- 94. Khader YS, Rice J, John L, Abueita O. Oral contraceptives use and the risk of myocardial infarction: a meta-analysis. Contraception. 2003;68(1):11–7. pmid:12878281
- 95. Gillum LA, Mamidipudi SK, Johnston SC. Ischemic stroke risk with oral contraceptives: a meta-analysis. JAMA. 2000;284(1):72–8.
- 96. Sidney S, Siscovick DS, Petitti DB, Schwartz SM, Quesenberry CP, Psaty BM, et al. Myocardial infarction and use of low-dose oral contraceptives: a pooled analysis of 2 US studies. Circulation. 1998;98(11):1058–63. pmid:9736591
- 97. Organización Mundial de la Salud. Planificación familiar [Internet]. Organización Mundial de la Salud. 2020 [cited 2022 Jan 21]. Available from: https://www.who.int/es/news-room/fact-sheets/detail/family-planning-contraception
- 98.
Family Planning: A Global Handbook for Providers. Baltimore and Geneva: World Health Organization Department of Reproductive Health and Research (WHO/RHR), Johns Hopkins Bloomberg School of Public Health/Center for Communication Program. 2022. pp. 1–460.
- 99. Bergendal A, Persson I, Odeberg J, Sundström A, Holmström M, Schulman S, et al. Association of venous thromboembolism with hormonal contraception and thrombophilic genotypes. Obstet Gynecol. 2014;124(3):600–9. pmid:25162263
- 100. Farmer RD, Lawrenson RA, Thompson CR, Kennedy JG, Hambleton IR. Population-based study of risk of venous thromboembolism associated with various oral contraceptives. Lancet. 1997;349(9045):83–8. pmid:8996419
- 101. Profamilia. Píldoras anticonceptivas de emergencia. [cited 2023 Oct 7]. Available from: https://profamilia.org.co/productos/anticonceptivos-de-emergencia/
- 102. Vademecum. Mirena Sistema de liberación intrauterino 20 µg/24 h de Colombia [Internet]. 2018 [cited 2021 Dec 7]. Available from: https://www.vademecum.es/equivalencia-lista-mirena+sistema+de+liberacion+intrauterino+20+µg%2F24+h-colombia-g02ba03-19002682-co_1