Oral Contraceptive Pills and Hypertension: A Review of Current Evidence and Recommendations

Abstract

Oral contraceptive pills (OCPs) have been used as effective and popular forms of contraception since the middle of the last century. By 2019, over 150 million reproductive-aged individuals were using OCPs to prevent unintended pregnancies worldwide. Safety concerns regarding the effects of OCPs on blood pressure were reported soon after these pills gained approval. Although OCP doses were subsequently reduced, epidemiologic evidence continued to support a smaller, but significant association between OCPs and hypertension. Given the rising prevalence of hypertension, as well as the adverse effects of cumulative exposure to blood pressure elevations on cardiovascular disease risk, understanding the nature of the association between OCPs and hypertension is important for clinicians and patients to assess the risks and benefits of use, and make individualized decisions regarding contraception. Therefore, this review summarizes the current and historical evidence describing the association between OCP use and blood pressure elevations. Specifically, it identifies the pathophysiologic mechanisms linking OCPs to hypertension risk, describes the magnitude of the association between OCPs and blood pressure elevations, and distinguishes the effects of various OCP types on blood pressure. Finally, it describes current recommendations regarding hypertension and OCP use, as well as identifies strategies, such as over-the-counter OCP prescribing, to safely and equitably improve access to oral contraception.

Introduction

Oral contraceptive pills (OCPs) are used commonly with growing popularity worldwide. From 1994 to 2019, the number of OCP users increased from 97 to 151 million with over 20% of reproductive-aged, pregnancy-capable individuals in 27 countries reporting use.¹ Although primarily used to prevent unintended pregnancies, OCPs can be prescribed for a variety of indications including: menstrual disorders, endometriosis and polycystic ovarian syndrome, and have been associated with lower risk of ovarian and endometrial cancer.² The decision to use OCPs, however, is individualized and must be carefully considered given reports of higher risk of hypertension (HTN), cardiovascular disease (CVD), and venous thromboembolism (VTE) among certain populations of OCP users. ^3–8 Given the low absolute risk of CVD in otherwise healthy, reproductive aged self-identifying women, while rare, the small magnitude of increase in blood pressure (BP) that can occur with OCP use is unlikely to be clinically significant. However, when a woman has multiple major risk factors, OCP use may increase her risk to an unacceptable level.⁹

HTN is one of the most common potential contraindications to OCP use. In the United States (US), approximately 10% of reproductive-aged, women have a systolic blood pressure (SBP) ≥ 140 or diastolic blood pressure (DBP) ≥ 90 and almost 20% have SBP ≥ 130 or DBP ≥ 80.¹⁰ Among those 20–34 years old, nearly 1-in-5 were unaware of a HTN diagnosis and more than 50% had uncontrolled HTN.¹¹ Given the excess CVD-risk associated with cumulative exposure to BP elevations,¹² understanding how OCP use may contribute to or exacerbate BP elevations is of particular importance in reproductive-aged individuals. Therefore, this review will summarize the current epidemiologic evidence describing the association between OCP use and BP elevations, explore the pathophysiologic mechanisms linking OCP use with HTN, and identify current recommendations regarding OCP use among those with a history of or at-risk of HTN.

Development and Classification of OCPs

History of oral contraception

The first clinical trials investigating OCPs were conducted in Puerto Rico in the 1950s when contraception was illegal in the US.¹³ Although initial trials utilized the synthetic progestin, norethynodrel, synthetic estrogens such as mestranol and ethinyl estradiol were later added to reduce the breakthrough bleeding observed with the progestin only formulation. In 1957, the US Food and Drug Administration (FDA) approved the first OCP, Enovid (mestranol 150 μg/norethynodrel 10mg), for treatment of menstrual disorders. Three years later, it was approved for contraceptive purposes, but its use was limited to married couples until 1972.^13,14

In less than one year after Enovid received FDA approval, 20 non-fatal and 6 fatal cases of VTE were reported among OCP users.¹⁵ With mounting epidemiologic evidence linking OCPs with higher risk of VTE and CVD, as well as subsequent work implicating estrogen in enhancing platelet aggregation and adhesiveness, doses of synthetic estrogens in OCPs were reduced to contain as little as 15–35 μg of ethinyl estradiol.^13,15,16 Over the past two decades, OCPs containing estradiol valerate (a prodrug of estradiol) and estetrol (a fetal estrogen) were developed based on the premise that these naturally occurring estrogens would have fewer associated adverse effects.^15,17,18 Phase III clinical trials have shown promising efficacy and safety data, however Phase IV trials are needed to determine if OCPs containing these natural estrogens reduce risk of VTE and CVD events.^19,20

As the estrogenic component of OCPs was reduced, the progestin component was modified to further promote more favorable side effect profiles. First generation progestins, such as norethindrone, were originally used in high doses and had potent off-target effects on androgen and glucocorticoid receptors, contributing to acne and adverse metabolic effects such as lower high-density lipoprotein levels.^13,15,21,22 The development of higher potency, second generation progestins, allowed for lower doses to be used. Third generation progestins were further chemically modified to reduce unwanted off-target effects at the androgen and glucocorticoid receptors.^13,21,22 Newer, fourth generation progestins such as drospirenone and dienogest have been designed to additionally promote anti-androgenic and/or anti-mineralocorticoid activity (Figure 1).²¹ Progestin only pills (POPs) containing norethindrone (first generation) or drospirenone (fourth generation) are available for contraceptive purposes, however, are associated with irregular bleeding and need to be taken at the same time each day.^23,24 Therefore, combined hormonal contraceptives (CHCs) have remained a more popular option in recent years.

Figure 1.

Summary of estrogens and progestins used in oral contraceptive pills. Natural estrogens and lower doses of synthetic estrogens are associated with lower blood pressure elevations. Drospirenone has blood pressure lowering effects.

Current Formulations of Combined Hormonal Contraception

The vast majority of currently available CHCs contain ≤ 50 μg of ethinylestradiol combined with a second, third or fourth generation progestin. CHCs are offered in multiple types of dosing regimens and formulations. These include monophasic dosing (same dose of hormones in each pill), multiphasic dosing (varying weekly hormone doses to mimic the menstrual cycle), cyclic formulations (active hormone pills for 21–24 days followed by placebo pills for 7–4 days), extended cyclic formulations (active hormone pills for 84 days followed by placebo pills for 7 days), or continuous formulations.²⁵

Evidence for Associations between Oral Contraception and Hypertension

Magnitude of the Association between Oral Contraceptive Pills and Hypertension

Cases of severe BP elevations after OCP initiation were first noted in the 1960s.^26,27 In an observational study of 16 individuals who developed HTN while taking CHCs, BP elevations were observed 3–36 months after CHC initiation with a mean BP of 170/100 mmHg. BP significantly declined in all patients within 2–6 months of CHC discontinuation.²⁸ Subsequent prospective, observational studies of individuals taking CHCs estimated average increases in SBP ranging from 7–17mmHg and in DBP from 3–11mmHg, with a HTN incidence of 4–18%.^29–32 Although these early studies established an association between CHC use and HTN, typical CHCs marketed in the 1960s and early 1970s contained substantially higher doses of estrogens and progestins than are used currently. Additionally, BP estimates in these studies did not account for underlying risk factors (i.e. age, body mass index, tobacco use) that may modify the relationship between CHC use and HTN.

In the 1990s-2010s, data from several large, cross-sectional studies conducted in the US, Europe and Asia, revealed smaller, but significant, elevations in BP associated with OCP use.^4,33–35 Among 68,297 individuals aged 25–42 years old enrolled in the Nurses’ Health Study in the US, SBP was higher by 0.7 mmHg (95% confidence interval [CI] 0.4 – 1 mmHg) and DBP by 0.4mmHg (95% CI 0.4 – 0.6 mmHg) among current OCP users, the vast majority of whom were CHC-users, compared with non-users after adjustment for age, ethnicity, parity, and CVD risk factors (body mass index, smoking behavior, physical activity and family history of HTN).⁴ After 4 years of follow-up, risk of incident HTN was higher by 1.9 (95% CI 1.6, 2.4) and 1.2 (95% CI 1.1, 1.5) times among current and past OCP-users, respectively. Of note, individuals included in this analysis were free from a history of HTN, CVD, diabetes or a recent pregnancy that may have been complicated by a hypertensive disorder at baseline. Cross-sectional studies using nationally-representative health survey data from England, Germany and Korea that did not exclude participants based on the presence of CVD or CVD risk-factors noted greater absolute BP elevations among OCP users compared with non-users with SBP higher by 2.6–5.8 mmHg and DBP by 1.8 – 3.6 mmHg.^33–35 Although these studies did not consistently report doses and types of OCPs, authors estimated that the majority were CHCs containing less than 50 μg of ethinyl estradiol based on consumer data available at the time.^33,35

Additional data from several large, observational studies further suggested that the presence of underlying CVD risk factors may amplify the effects of OCPs on BP. Compared with individuals using CHCs who did not have risk factors, individuals with a self-reported family history of HTN, older age (35–44 years old) and obesity were observed to have 2-, 3- and 6-times the risk of developing HTN, respectively.^36–38 Although data regarding the interaction between age and OCP use on HTN risk are mixed, some have suggested that null results may be a consequence of selection bias resulting from the tendency to avoid OCPs among individuals 35 years and older, particularly among those with a history of HTN or other CVD risk factors.^4,33,39 Hypertensive disorders of pregnancy, known risk-factors for CVD, have also been implicated in enhancing the BP effects of OCPs.^40,41 Several studies demonstrated higher BPs and higher prevalence of HTN among OCP users with a history of hypertensive disorders of pregnancy, however, studies were small and conducted among early users of OCPs.^30,31,39,42 Larger scale, population-level work is needed to quantify HTN risk among patients on OCPs with a history of hypertension in pregnancy.

Duration of Oral Contraceptive Pills use and HTN Risk

Current epidemiologic evidence from large-scale observational studies of primarily CHC users suggest that cumulative use of OCPs may be associated with higher risk of HTN. Cross-sectional data from the Korea National Health and Nutrition Examination Surveys (KNHANES) from 2007–2009 demonstrated higher odds of HTN with every one additional year of OCP use with the highest odds noted among those taking OCPs for two or more years (OR 1.96 [95% CI 1.03, 3.37]).³⁵ Similarly, risk of incident HTN over the 4-year follow-up period in the Nurses’ Health Study was higher among OCP users compared with non-users after 2-years of reported use. Although absolute risk of incident HTN was higher with each additional 2-years of OCP use up to ≥ 6 years thereafter, trends were not significant, possibly due to the low incidence of HTN in this population (0.5–1.9%) and small sample sizes within subgroups.⁴

Studies recording longer cumulative OCP use have continued to demonstrate significant associations between duration of use and HTN risk. In a case-control study from China that reported more than 20 years of OCP-use, every additional 5 years of use was associated with higher odds of HTN.³⁶ Analogously, individuals who discontinued OCPs greater than 15–20 years prior to the study were approximately 60% less likely to have HTN than were current OCP uers.³⁶ Pooled data from a meta-analysis of 24 studies including 270,284 participants from Asia, Europe, North America and Oceania, reported similar results describing a 13% higher risk of HTN for every 5-years of OCP use.⁴³ However, between-study heterogeneity was high as data from included studies were collected from the 1970s – 2000s. Although doses and formulations of OCPs were not recorded, they likely varied substantially given the range of years from which data were reported.

Influence of Hormonal Components of Oral Contraceptive Pills on Blood Pressure

Given that OCP types were not described in many of the aforementioned observational studies, the differential effects of the estrogen and progestin components in CHCs are less clear from these data. Several cross-sectional and prospective studies have demonstrated that POPs are not associated with elevated BP,^33,44–47 suggesting that the estrogen component may primarily be responsible for blood pressure changes among individuals taking CHCs. BP elevations have been observed among individuals taking CHCs containing ethinyl estradiol at doses ranging from less than 30 μg to greater than 50 μg when combined with first, second and third generation progestins at various doses.^{4,29,32,39,47–49} At low (≤ 30 μg) and moderate ( > 30 – 50 μg) doses of ethinyl estradiol, risk of HTN may not be dose dependent,⁴ however comparative studies with CHCs containing > 50 μg are lacking given that estrogen doses were reduced in the early 1970s.

Although POPs are not associated with increases in BP, some have hypothesized that progestins may enhance the effects of estrogen on BP through off-target effects on the androgen and estrogen receptors.^39,50 In a cross-sectional study of individuals taking OCPs with ethinyl estradiol 30 μg and levonorgestrel (a progestin with activity at both the androgen and estrogen receptors), SBP was higher among individuals using OCPs with levonorgestrel 250 μg (113.7 mmHg) compared with levonorgestrel 150 μg (111.4 mmHg), however, differences were not significant.³⁹ Additional work comparing BP among individuals taking CHCs with varying doses of first, second and third generation progestins, have not observed significant differences in BP elevations between groups, however a higher risk of venous thromboembolism has been shown when newer generation progestins are co-administered with ethinyl estradiol.^{32,47–49,51,52}

New Oral Contraceptive Pills: Drospirenone and Natural Estrogens

One of the newest progestins, drospirenone, has shown promise in mitigating, and even reversing, the adverse effects of OCPs on BP through its anti-mineralocorticoid effects. Among 72 individuals living in Turkey aged 20–35 years old without a history of hypertension, mean SBP significantly decreased from 109.2 mmHg to 103.4 mmHg after 12 months of using a CHC containing ethinyl estradiol 30 μg and drospirenone 3 mg.⁵³ Other studies from Germany and India have demonstrated absolute declines in SBP of 1–4 mmHg after 6 months of ethinyl estradiol 15–30μg combined with drospirenone 3mg.^54,55 When administered as a POP, drospirenone 4mg is associated with decreases in SBP of 8 mmHg and DBP of 5 mmHg among individuals with baseline SBP ≥ 130 and DBP ≥ 85, and stable BPs among normotensive individuals.^56,57

The newest CHCs in the US contain the natural estrogens estradiol valerate and estetrol combined with dienogest and drospirenone, respectively. In a pooled analysis of two multicenter, open-label phase 3 trials, estetrol 15mg/drospirenone 3mg was not associated with changes in BP after 13 cycles of use; HTN incidence attributable to drug use was 0.2%.⁵⁸ Similarly, significant changes in BP, as measured by ambulatory BP monitoring, were not observed after 6 months of estradiol valerate/dienogest.⁵⁹ While these studies suggest that natural estrogens may have less adverse BP effects than do synthetic estrogens such as ethinyl estradiol, data from larger trials powered to detect differences in BP between different formulations of CHCs are needed.

Pathophysiology of Associations between Oral Contraceptive Pills and Hypertension

The Renin-Angiotensin-Aldosterone System

The renin-angiotensin-aldosterone system (RAAS) has long been implicated in the association between OCP use and HTN. Briefly, RAAS regulates BP via a negative feedback loop with downstream effects on renal sodium and water reabsorption, systemic arteriolar vasomotor activity and sympathetic nervous system activation (Figure 2). The RAAS cascade is initiated in response to decreases in BP, reductions in the delivery of sodium chloride to the macula densa of the distal convoluted tubule and stimulation of renal sympathetic nerves.⁶⁰ When the system is activated, renin is released from the kidneys and converts hepatic angiotensinogen to angiotensin I. The angiotensin converting enzyme (ACE) then converts angiotensin I to angiotensin II which elevates BP by increasing sodium reabsorption in the proximal convoluted tubule, promoting systemic arteriolar vasoconstriction, activating the sympathetic nervous system, increasing thirst, and stimulating the release of aldosterone from the adrenal cortex and antidiuretic hormone from the pituitary.^60,61

Figure 2.

Mechanisms through which estrogens in oral contraceptive pills may increase blood pressure. This diagram illustrates the renin-angiotensin-aldosterone system and shows the potential sites of action for estrogens, including through increased hepatic production of angiotensinogen, impaired negative feedback regulation of renin, altered regulation of antidiuretic hormone release via resetting of osmoreceptors, and impaired baroreceptor regulation. Figure created with BioRender.com.

Estrogen and Activation of the Renin-Angiotensin-Aldosterone System

One leading hypothesis stipulates that estrogen stimulates hepatic production of angiotensinogen leading to RAAS activation.^62–64 Supporting this hypothesis, several small studies published in the 1960s-70s noted an association between OCP use and higher levels of plasma angiotensinogen, plasma renin activity, angiotensin I, angiotensin II and aldosterone.^28,65–68 Later work suggested that the effects of OCPs on RAAS may be dose-dependent. In a randomized, prospective study of 72 individuals, plasma angiotensinogen levels doubled among individuals taking CHCs containing ethinyl estradiol 50mcg, while levels increased by approximately 12–20% among those taking OCPs containing ethinyl estradiol 30–35mcg.⁶⁹ Downstream renovascular effects including higher renal vascular resistance, lower renal blood flow and higher filtration fraction have also been noted among individuals taking OCPs.^66,70,71 Administration of RAAS blocking agents to these individuals attenuated these changes, suggesting that the renovascular effects are RAAS mediated.^70,71

Impaired Regulation of the Renin-Angiotensin-Aldosterone System

Although this body of work has supported an association between OCP use and RAAS activation, changes in RAAS have been noted in OCP users regardless of their BP status.^67,71 This suggests that RAAS activation is not the only mechanism explaining the effects of OCPs on BP. Some have hypothesized that OCPs impair feedback inhibition of RAAS. In a functional feedback loop, estrogen mediated RAAS activation should induce negative feedback and decrease plasma renin production. Several studies have demonstrated higher levels of plasma renin concentration among OCP users with elevated BPs, suggesting impaired feedback inhibition.^31,72 However, results are not consistent between studies and may differ based on OCP dosing, duration of use and timing of measurement during the menstrual cycle.^63,68,72 Others have suggested that OCPs contribute to increases in BP via impaired regulation of muscle sympathetic nerve activity (MSNA) and antidiuretic hormone release.^73–75 MSNA is a regulator of vasomotor activity in the vascular smooth muscle of skeletal muscle, and has been shown to be present in similar concentrations among those with elevated BP using OCPs and among those with lower BP not taking OCPs.^73,76 These results suggest that OCPs may impair the ability of baroreceptors to reduce MSNA when blood pressure is elevated.⁷³ Similarly, OCPs may reset the osmoreceptors that regulate antidiuretic hormone release, as suggested by data demonstrating similar levels of antidiuretic hormone despite lower plasma osmolality and lower plasma sodium levels among OCP users compared with non-users.⁷⁵ More data are needed, however, to determine if these mechanisms explain changes in BP among OCP users.

Genetic Polymorphisms

It is also hypothesized that the presence of specific genetic polymorphisms may predispose some individuals to OCP-induced HTN. Higher frequencies of the 235T allele of the angiotensinogen gene have been observed among individuals using OCPs who develop HTN compared with those who do not. It is thought that this genetic variation may enhance the plasma angiotensinogen response to estrogen.^77,78 Others have suggested that genetic polymorphisms involving the estrogen beta receptor gene may enhance the effects of CHCs to elevate blood pressure.⁷⁹ However, mechanisms are still unclear, and additional work must clarify how OCPs incur both short- and long-term risk of HTN.

Estetrol

Of note, estetrol, a natural estrogen, may have less effects on the RAAS system compared with ethinyl estradiol. Estetrol is produced in the fetal liver and is naturally present during pregnancy starting at approximately 9-weeks of gestation; commercially, it is produced from soy estrone.⁸⁰ Compared with estradiol, which contains two hydroxyl groups, estetrol contains four hydroxyl groups and binds to the to the estrogen-α receptor with 4–5 times the affinity than to the estrogen-ß receptor.^18,80 Additionally, given that estetrol induces nuclear activity, but not membrane-initiated steroid signaling, it acts selectively at different tissues as either an agonist (ex. brain, bone, uterus) or antagonist (ex. breast).⁸⁰ In the liver, it has limited effects on the genetic expression and production of coagulation factors and angiotensinogen, therefore contributing to a lower thrombogenic potential and less downstream effects on RAAS, respectively.⁸⁰ In a randomized, open-label, 3-arm study, angiotensinogen increased less among estetrol/drospirenone users (75% increase) compared with ethinyl estradiol/drospirenone users (170% increase) and ethinyl estradiol/levonorgestrel users (206% increase), which may mitigate the effects of the estrogenic component of CHCs on blood pressure.⁸¹ In addition, estetrol activates membrane estrogen- α of vascular endothelial cells which contributes to nitric oxide production and vasodilation, which may prevent neointimal proliferation and hypertension.¹⁸

Oral Contraceptive Pills, Hypertension and Cardiovascular Disease

Ample evidence supports an association between current OCP use and cardiovascular disease (CVD) including acute myocardial infarction, ischemic stroke and peripheral artery disease, with higher rates noted among older individuals on higher doses of synthetic estrogens (≥ 50 mcg).^3,7,82–86 Concomitant HTN may amplify the effects of OCP use on CVD risk. In four case-control studies, odds of myocardial infarction were 6.1 – 68.1 times higher among individuals with HTN using OCPs, 5.4 – 9.5 times higher among those with HTN alone and 2.0 – 3.9 times higher among those without HTN using OCPs compared with individuals free from HTN or OCP use.^3,5–7,87 For individuals with a history of HTN during pregnancy using OCPs, absolute risk of myocardial infarction was approximately 2-times that of those using OCPs without a history of a hypertensive disorder of pregnancy.³ Although sample sizes among OCP-HTN subgroups were small in these studies such that confidence intervals overlapped, pooled data from a meta-analysis showed significant differences with odds of myocardial infarction 9.30 (95% CI 3.89–22.23) times higher among those with HTN and OCP use compared with 2.48 (1.91, 3.22) times among all OCP users compared with normotensive, non-OCP users.⁸⁶

Risk of ischemic stroke and peripheral artery disease are similarly high among individuals with HTN taking OCPs with odds ranging from 8 – 15 times that of those without HTN or OCP use.^82,83 Although absolute risk of ischemic stroke and peripheral artery disease among OCP users with HTN are approximately 1.5 – 2 times that of those with either HTN or OCP-use alone, there is likely not a true interaction.⁸⁸ In case-control studies, confidence intervals comparing stroke and peripheral artery disease risk among those with HTN and OCP use with individuals with either risk factor, overlap.^82,83,88 Furthermore, a meta-analysis of 16 studies did not find significant changes in risk associated with HTN and OCP use compared with OCP use alone.⁸⁹

Of note, risk of CVD has not been shown to be higher among individuals taking POPs. In the World Health Organization (WHO) Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception, a case-control study with data from 17 countries, odds of CVD (stroke, VTE or acute myocardial infarction) were not higher among POP users (OR 1.19 [95% CI 0.82, 1.74]). Among participants with HTN, absolute odds of stroke were higher among POP users (OR 10.9 [3.55, 33.80]) compared with non-users (7.2 [6.1, 8.5]), however, differences were not significant. Furthermore there was no interaction observed between HTN and POP use in the risk of acute myocardial infarction or VTE.⁹⁰

Clinical Recommendations for Oral Contraceptive Pill Use

Initiation of Oral Contraceptive Pills

The WHO Medical Eligibility Criteria (MEC) specify recommendations for the initiation of OCPs by underlying medical condition.⁹¹ Recommendations are classified on a scale of 1 through 4 with 1 representing “no restrictions” and 4 representing “unacceptable health risks” to use (Table 1).^9,91 These criteria are endorsed by the Centers for Disease Control and the American College of Obstetricians and Gynecologists (ACOG), as well as adapted by guidelines in Canada and the United Kingdom.^9,92–94 Table 1 shows the MEC for use of POPs and CHCs.⁹ POPs are generally considered safe to use among individuals with HTN. Given high risk of CVD and stroke among individuals with HTN using CHCs, the MEC designate a class 3 risk (risks usually outweigh the benefits) for CHC use among individuals with “adequately controlled HTN” or with SBP 140–159 mmHg or DBP 90–99 mmHg, and a class 4 risk (unacceptable health risk) for those with SBP ≥ 160 mmHg or DBP ≥ 100 mmHg. For individuals with normal BPs, but a history of high blood pressure during pregnancy, the advantages of CHC use are felt to generally outweigh the risks (MEC 2). Of note, these recommendations assume the absence of other CVD risk factors. Additional caution should be taken among those with other CVD risk factors such as obesity, tobacco use or adverse cholesterol profiles.^{9,91,92,94,95} Furthermore, these recommendations do not reflect the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) updated HTN guidelines specifying a diagnostic threshold for HTN of SBP ≥ 130 or DBP ≥ 80.⁹⁶ ACOG recognizes this discrepancy, but recommends continued use of the current MEC criteria given lack of data evaluating risk of CVD and stroke among OCP users with HTN as defined by the new ACC/AHA guidelines.⁹²

Table 1.

Medical Eligibility Criteria^* for Contraceptive Use for Individuals with Hypertension^†,‡

	Combined Hormonal Contraceptives	Progestin Only Pills
Hypertension
Adequately Controlled Hypertension§	3	1
Systolic Blood Pressure 140–159 or Diastolic Blood Pressure 90–99	3	1
Systolic Blood Pressure ≥ 160 or Diastolic Blood Pressure ≥ 100	4	2
Hypertension Associated with Vascular Disease	4	2
History of High Blood Pressure During Pregnancy
When current blood pressure is measurable and normal	2	1
Multiple Risk Factors for Atherosclerotic Cardiovascular disease ||
E.g. Older age, smoking, diabetes, hypertension, dyslipidemia	3/4	2

1	No restriction for the use of the contraceptive method for a woman with that condition
2	Advantages of using the method generally outweigh the theoretical or proven risks
3	Theoretical or proven risks of the method usually outweigh the advantages – not usually recommended unless more appropriate methods are not available or acceptable
4	Unacceptable health risk if the contraceptive method is used by a woman with that condition

^*Medical Eligibility Criteria Categories:

^†Adapted and printed with permission from U.S. Medical Eligibility Criteria for Contraceptive Use. Centers for Disease Control and Prevention; 2016. Accessed October 17, 2022. https://www.cdc.gov/reproductivehealth/contraception/pdf/summary-chart-us-medical-eligibility-criteria_508tagged.pdf

^‡For all categories of hypertension, classifications are based on the assumption that no other risk factors exist for cardiovascular disease. When multiple risk factors do exist, risk for cardiovascular disease might increase substantially. A single reading of blood pressure level is not sufficient to classify an individual as hypertensive.

^§Individuals adequately treated for hypertension are at reduced risk for acute myocardial infarction and stroke compared with untreated individuals. Although no data exist, combined hormonal contraception and progestin only pill users with adequately controlled and monitored hypertension should be at reduced risk for acute myocardial infarction and stroke compared with untreated hypertensive users.

^||When an individual has multiple major risk factors, any of which alone would substantially increase their risk for cardiovascular disease, use of combined hormonal contraceptives might increase their risk to an unacceptable level. However, a simple addition of categories for multiple risk factors is not intended.

It is important to note that ACOG emphasizes that counseling regarding contraceptive choice should be balanced against the potential risk of unintended pregnancy, especially among individuals with underlying CVD risk-factors. Entering pregnancy with CVD risk-factors such as hypertension and/or obesity is associated with substantially higher pregnancy-related morbidity and mortality.^97–99 Furthermore, although risk of VTE is approximately 1.3–1.5 times higher among individuals using OCPs, risk is 3–10 times higher during pregnancy.^8,100 Therefore, the risks and benefits of OCP use must be weighed against those associated with unintended pregnancy and the availability of alternative contraceptive options.

Blood Pressure Monitoring During Oral Contraceptive Use

Medical society guidelines from Canada, Europe and the United States recommend that individuals have a BP check prior to initiation of CHC.^{94,95,101,102} This recommendation is based on evidence demonstrating higher risk of myocardial infarction and stroke among individuals without BP checks prior to CHC initiation.⁹¹ Once OCPs are started, BP should be monitored at follow-up or routine visits with the frequency of recommended checks ranging from every 6 months to annually, depending on the society guideline (Table 2).^{92,94,95,101,103} If BP increases significantly without another identifiable cause, ACOG recommends that the CHC be discontinued.⁹² BP monitoring is not generally recommended during POP use.⁹²

Table 2.

Guidelines for blood pressure monitoring prior to and during use of combined hormonal contraceptive pills recommended by medical society guidelines in Canada, Europe, and the United States

Medical Society	Recommended a blood pressure check prior to initiation of a combined hormonal contraceptive pill	Recommended frequency of blood pressure monitoring after initiation of a combined hormonal contraceptive pill
American College of Obstetricians and Gynecologists	Yes*	At “follow-up visits” among individuals without a history of hypertension. Recommends close monitoring after the first several months of initiation if starting in individuals with adequately controlled hypertension†
Centers for Disease Control‡	Yes	At “routine visits”
The Faculty of Sexual and Reproductive Healthcare of the Royal College of the Obstetricians and Gynaecologists§	Yes	Annually
German, Austrian and Swiss Societies for Gynecology and Obstetrics||	Not specified	Every 6 months in individuals not at risk for arterial thromboembolic events. For individuals with “borderline values” frequency of monitoring should depend on the prescribing physician
Society of Obstetricians and Gynecologists of Canada#	Yes	Not specified

^*Supported in Committee Opinion on Over-the-Counter Access to Hormonal Contraception: ACOG Statement on FDA Submission for Over-the-Counter Access to Contraception. Accessed October 24, 2022. https://www.acog.org/news/news-releases/2022/07/acog-statement-on-fda-submission-for-over-the-counter-access-to-contraception

^†ACOG Practice Bulletin No. 206: Use of Hormonal Contraception in Women With Coexisting Medical Conditions. Obstet Gynecol. 2019;133(2):e128-e150

^‡Centers for Disease Control and Prevention. (2019, October 6). Combined Hormonal Contraceptives. Accessed October 17, 2022 https://www.cdc.gov/reproductivehealth/contraception/mmwr/spr/combined.html

^§FSRH Clinical Guideline: Combined Hormonal Contraception (January 2019, Amended November 2020). Accessed October 17, 2022. https://www.fsrh.org/standards-and-guidance/documents/combined-hormonal-contraception/

^||Franik S, Bauersachs R, Beyer-Westendorf J, et al. Hormonal Contraception. Guideline of the DGGG, OEGGG and SGGG (S3 Level, AWMF Registry Number 015/015, January 2020). Geburtshilfe Frauenheilkd. 2021;81(2):152–182.

^#Black A, Guilbert E, Costescu D, et al. No. 329-Canadian Contraception Consensus Part 4 of 4 Chapter 9: Combined Hormonal Contraception. J Obstet Gynaecol Can. 2017;39(4):229–268.e5.

Over-the-Counter Oral Contraceptive Pill Prescribing

The American Academy of Family Physicians, ACOG and the American Medical Association have each released statements supporting over-the-counter access to OCPs.^{102,104–106} By reducing barriers to effective contraceptive methods, this recommendation aims to mitigate unintended pregnancy rates and empower pregnancy-capable individuals to assume control in their reproductive health.¹⁰⁴ Globally, 70% of countries permit over-the-counter access to OCPs without a prescription.¹⁰⁷ In the US, 17 states support pharmacist-led OCP prescribing, although policies regarding pharmacist training and requirements for physician follow-up vary by state.¹⁰⁸ In July, 2022 the US FDA received its first application for over-the-counter access to POPs.¹⁰⁴

Although over-the-counter access to OCPs could be an important step to promoting reproductive justice, ACOG acknowledges that such reform would require that individuals be screened for potential contraindications to OCP-use, including HTN.¹⁰² Without the use of checklists, unaided self-screening has relatively poor sensitivity and specificity (83% and 89%, respectively) for the identification of contraindications to OCP use. ¹⁰⁹ The majority of missed contraindications are attributable to unrecognized HTN.¹⁰⁹ Data from CHC users in Mexico, where there are no standard practices for contraindication screening for over-the-counter OCPs, demonstrated that 9.8% of over-the-counter CHC-users had HTN compared with 5% of clinic-users.¹¹⁰ Therefore, standardized practices to identify contraindications to OCPs are needed to ensure safety of use. Several strategies including pharmacist-led screening and self-measured blood pressure monitoring (SMBP) via checklists and online tools have shown some promise in successfully identifying contraindications prior to use.^102,111 ACOG suggests that HTN screening prior to OCP-use could be fulfilled via SMBP, in-person measurements at the prescribing pharmacy or with evidence of a recent BP check at a physician’s office.¹⁰²

Another important consideration regarding over-the-counter OCP use is if and how it could address current sociodemographic disparities in unintended pregnancies in the US. Rates of unintended pregnancies are approximately 65% among those with an income less than 100% of the federal poverty line and over 50% among those without a college education in the US.¹⁰⁰ Compared with non-Hispanic White individuals, non-Hispanic Black individuals report almost 2-times the prevalence of unintended pregnancies.^112,113 Given that differences in access to contraceptive methods likely contributes to some of these disparities, expanding current policies to allow over-the-counter OCP-use could potentially reduce these gaps in unintended pregnancies.¹¹⁴ However, increasing access alone would not wholly address the influence of structural and historical racism.¹¹⁵ Legalized, coercive sterilization practices have historically disproportionally affected low-income, Black, Latina and American Indian individuals, generating a deeply rooted mistrust in contraception and the medical profession that persists to present day.^115,116 Increasing access to contraception through over-the-counter and pharmacist-led efforts will likely not successfully promote utilization unless coupled with public health efforts to confront the repercussions of historical racism.¹¹⁵ Furthermore, given that the highest rates of OCP contraindications, including HTN, are observed among groups with the highest unintended pregnancy rates (i.e. individuals from low-income households and without a high school education), special care must be taken to ensure equity in contraindication screening.¹¹⁷ Additional work is needed to identify and implement culturally-competent and language-congruent strategies for risk-factor and HTN screening prior to over-the-counter OCP-use.

Conclusion

OCPs are widely used globally and important for preventing unintentional pregnancies. Epidemiologic evidence has long supported an association between OCP use and BP elevations which is thought to be mediated through the estrogenic component’s effect on RAAS, although mechanisms are still unclear. Newer formulations of OCPs containing natural estrogens and progestins with anti-mineralocorticoid effects (i.e. drospirenone) may mitigate or even reverse the association between OCP use and BP elevations. Given that additional data are needed to confirm the influence of these new OCPs on BP, current guidelines recommend that CHCs be avoided in individuals with HTN, although POPs are thought to be safe. Expanding access to OCPs through over-the-counter and pharmacist-led prescribing, will require standardized guidelines for contraindication screening, including HTN, that are equitably implemented and distributed.