Combined hormonal contraceptive use among women with known dyslipidemias: a systematic review of critical safety outcomes.

Dyslipidemias represent a spectrum of lipid disorders that are important risk factors for cardiovascular disease. In addition, elevated triglycerides are known to be associated with pancreatitis. Though less clear, it is possible that dyslipidemias may also contribute to risk for venous thromboembolism (VTE). Ethinyl estradiol and progestogen, contained within combined hormonal contraception, are known to impact lipid metabolism. To evaluate from the literature whether use of combined hormonal contraception (CHC), including combined oral contraception (COC) pills, transdermal patch, vaginal ring or injectables, modifies the relative risk of acute myocardial infarction (MI), stroke, VTE or pancreatitis among women with known dyslipidemias and to determine if existing lipid abnormalities worsen with CHC use. PubMed and the Cochrane Library databases were searched for all articles in all languages published between inception and September 2014 relevant to dyslipidemia, CHC use and serious adverse events (MI, stroke, VTE or pancreatitis). The quality of each individual study was assessed using the system for grading evidence developed by the United States Preventive Services Task Force. From 306 articles identified by our search strategy, 3 articles met inclusion criteria. In a poor-quality case-control study, women with hypercholesterolemia but no COC use had an increased risk of MI (adjusted odds ratio [adj OR] 3.3, 95% confidence interval [CI] 1.6-6.8), as did women who used COCs but did not have hypercholesterolemia (adj OR 2.0, 95% CI 1.4-2.8), compared with non-COC users without hypercholesterolemia; women with both COC use and hypercholesterolemia had an adjusted OR of 24.7 (95% CI 5.6-108.5) compared with women with neither risk factor. A poor-quality cohort study examined COC users and reported that women with dyslipidemia had increased risk for VTE [crude risk ratio (RR) 1.39, 95% CI 1.04-1.85] and transient ischemic attacks or cerebrovascular accidents (CVAs) (RR 1.76, 95% CI 1.51-2.06) compared to those without dyslipidemia. Another poor-quality cohort study provided direct evidence on changes in lipid levels among COC users with dyslipidemia. A minority of women with elevated total cholesterol or triglyceride levels at baseline showed normal results (25% and 28%, respectively) after 6 cycles of COC use. No evidence regarding risks associated with use of other CHC methods was identified. No evidence was identified for the outcome of pancreatitis. Limited data from poor-quality observational studies suggest that women with known dyslipidemias using CHC may be at increased risk for MI and may experience a minimal increase in risk for CVA or VTE. No evidence was identified on risk for pancreatitis in this context. The impact of CHC exposure on the status of lipid abnormalities over time, an intermediate marker for disease, is also unclear. Given the significant limitations of this body of evidence, the importance of access to effective contraception and theoretical concerns raised about the use of CHCs by women with known dyslipidemias, additional rigorous studies are needed to best estimate true associations. Contraceptive decision making should include consideration of both the known and theoretical risks of a given CHC method, safety and acceptability of alternative contraceptive methods, and risks associated with unintended pregnancy.

Dragoman M ，Curtis KM ，Gaffield ME 《-》

Combined hormonal contraceptive use among obese women and risk for cardiovascular events: A systematic review.

Combined hormonal contraceptive (CHC) use may modify the risk of cardiovascular events in obese [body mass index (BMI) ≥30kg/m2] women. The objective was to evaluate from the literature whether CHC use modifies the risk of acute myocardial infarction (AMI), stroke, cerebral venous thrombosis (CVT) and venous thromboembolism (VTE) in obese women and to evaluate evidence for a dose-response relationship between BMI and VTE. We searched PubMed for all articles published between database inception and February 2016 providing direct evidence on BMI, CHCs, and cardiovascular outcomes. We also searched for indirect evidence related to a dose-response relationship between BMI and risk of VTE in the general population, as these data were lacking for CHC users. The quality of each individual study was assessed using the system for grading evidence developed by the United States Preventive Services Task Force. The direct evidence search yielded 3 pooled analyses, 11 case-control studies and 1 cohort study. There was conflicting evidence about the risk of AMI or stroke among obese combined oral contraceptive (COC) users compared to obese nonusers, with one study finding no increased risk for AMI or stroke for COC users overall or stratified by BMI. A second study found significantly increased risk of AMI and stroke for COC users, with the highest risk estimates for high-BMI COC users. A single study suggested that obese COC users may be at higher risk for CVT compared with normal-weight nonusers. For VTE, obese COC users consistently had a risk that was 5 to 8 times that of obese nonusers and approximately 10 times that of nonobese nonusers. Five prospective cohort studies were identified as indirect evidence, and all found increased risk for VTE as BMI increased, suggesting a dose-response relationship between BMI and risk for VTE. No studies on the contraceptive patch or vaginal ring were identified that met the inclusion criteria. Limited evidence of Level II-2, fair quality, concerning whether CHC use modifies the risk of AMI and stroke in obese women is inconclusive, while a single study of Level II-2, poor quality, found that obese COC users may be at higher risk for CVT compared with normal-weight nonusers. Both COC use and higher BMI increase risk for VTE, and the greatest relative risks are for those with both risk factors based on a body of evidence graded as Level II-2, fair to poor quality. It is not possible to estimate absolute risk of VTE among women with both of these risk factors; however, the absolute risk of VTE in healthy women of reproductive age is small.

Horton LG ，Simmons KB ，Curtis KM 《-》

Nonoral combined hormonal contraceptives and thromboembolism: a systematic review.

Combined hormonal contraceptives (CHCs), containing estrogen and progestin, are associated with an increased risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) compared with nonuse. Few studies have examined whether nonoral formulations (including the combined hormonal patch, combined vaginal ring and combined injectable contraceptives) increase the risk of thrombosis compared with combined oral contraceptives (COCs). The objectives were to examine the risk of VTE and ATE among women using nonoral CHCs compared to women using COCs. We searched the PubMed database for all English language articles published from database inception through May 2016. We included primary research studies that examined women using the patch, ring or combined injectables compared with women using levonorgestrel-containing or norgestimate-containing COCs. Outcomes of interest included VTE (deep venous thrombosis or pulmonary embolism) or ATE (acute myocardial infarction or ischemic stroke). We assessed the quality of each individual piece of evidence using the system developed by the United States Preventive Services Task Force. Eight studies were identified that met inclusion criteria. Of seven analyses from six studies examining VTE among patch users compared with levonorgestrel- or norgestimate-containing COC users, two found a statistically significantly elevated risk among patch users (risk estimates 2.2-2.3), one found an elevated risk that did not meet statistical significance (risk estimate 2.0), and four found no increased risk. Of three studies examining VTE among ring users compared with levonorgestrel COC users, one found a statistically significantly elevated risk among patch users (risk estimate 1.9) and two did not. Two studies did not find an increased risk for ATE among women using the patch compared with norgestimate COCs. We did not identify any studies examining combined injectable contraceptives. Limited Level II-2 good to fair evidence demonstrated conflicting results on whether women using the patch or the ring have a higher risk of VTE than women using COCs. Evidence did not demonstrate an increased risk of ATE among women using the patch. Overall, any potential elevated risk likely represents a small number of events on a population level. Additional studies with standard methodology are needed to further clarify any associations and better understand mechanisms of hormone-induced thrombosis among users of nonoral combined hormonal contraception.

Tepper NK ，Dragoman MV ，Gaffield ME ，Curtis KM ... -  《-》

Combined hormonal contraceptive use among breastfeeding women: an updated systematic review.

Contraception is important for women who are postpartum, including those who are breastfeeding. Use of combined hormonal contraceptives (CHCs) may affect breastfeeding performance and infant health outcomes. The objective was to identify evidence examining clinical outcomes for breastfeeding and infant health among breastfeeding women using CHCs compared to nonusers. We searched the PubMed database for all articles published from database inception through September 30, 2014. We included primary research studies that compared breastfeeding women using CHCs with breastfeeding women using nonhormonal or no contraception, or compared breastfeeding women initiating combined hormonal contraception at early versus later times postpartum. Breastfeeding outcomes of interest included duration, rate of exclusive breastfeeding and timing of supplementation. Infant outcomes of interest included growth, health and development. Fifteen articles describing 13 studies met inclusion criteria for this review. Studies ranged from poor to fair methodological quality and demonstrated inconsistent effects of combined oral contraceptives (COCs) on breastfeeding performance with COC initiation before or after 6 weeks postpartum; some studies demonstrated greater supplementation and decreased breastfeeding continuation among COC users compared with nonusers, and others demonstrated no effect. For infant outcomes, some studies found decreases in infant weight gain for COC users compared with nonusers when COCs were initiated at <6 weeks postpartum, while other studies found no effect. None of the studies found an effect on infant weight gain when COCs were started after 6 weeks postpartum, and no studies found an effect on other infant health outcomes regardless of time of COC initiation. Limited evidence of poor to fair quality demonstrates an inconsistent impact of COCs on breastfeeding duration and success. The evidence also demonstrated conflicting results on whether early initiation of COCs affects infant outcomes but generally found no negative impact on infant outcomes with later initiation of COCs. The body of evidence is limited by older studies using different formulations and doses of estrogen and poor methodologic quality. Given the significant limitations of this body of evidence, the importance of contraception for postpartum women and the theoretical concerns that have been raised about the use of combined hormonal contraception by women who are breastfeeding, rigorous studies examining these issues are needed. In addition, postpartum women should be counseled about the full range of safe alternative contraceptive methods, particularly during the first 6 weeks postpartum when the risk of venous thromboembolism is highest and use of estrogen may exacerbate this risk.

Tepper NK ，Phillips SJ ，Kapp N ，Gaffield ME ，Curtis KM ... -  《-》

Safety of hormonal contraceptives among women with migraine: A systematic review.

Migraine is common among women of reproductive age and is associated with an increased risk of ischemic stroke. Combined oral contraceptives (COCs) are also associated with an increased risk of ischemic stroke. Use of hormonal contraception among women with migraine might further elevate the risk of stroke among women of reproductive age. To identify evidence regarding the risk of arterial thromboembolism (stroke or myocardial infarction) among women with migraine who use hormonal contraceptives. We searched the PubMed database for all articles published from database inception through January 2016. We included studies that examined women with migraine overall or separated by subtype (with or without aura). Hormonal contraceptives of interest included combined hormonal methods (COCs, patch and ring) and progestin-only methods (progestin-only pills, injectables, implants and progestin intrauterine devices). Seven articles met inclusion criteria. All were case-control studies of fair to poor quality reporting on use of COCs or oral contraceptives (OCs) not further described and all reported stroke outcomes. Four studies demonstrated that, among women with migraine (not separated by subtype), COC use was associated with approximately two to four times the risk of stroke compared with nonuse. The only study to examine specific migraine subtypes found an elevated risk of stroke among women with migraine with aura, and this risk was similar regardless of OC use, although these odds ratios were not reported. Two studies did not report risks among women with migraine and COC use combined, but both found increased risks of stroke with migraine and COC use independently. No evidence was found on other hormonal contraceptives or on risk of myocardial infarction. Limited evidence suggests a two- to fourfold increased risk of stroke among women with migraine who use COCs compared with nonuse. Additional study is needed on the risks of hormonal contraceptives, including combined and progestin-only methods, among women with different migraine subtypes.

Tepper NK ，Whiteman MK ，Zapata LB ，Marchbanks PA ，Curtis KM ... -  《-》