Discussion
Obesity defined as a body mass index ≥ 30 kg/m2 has been found to affect 38.3% of US women between the years of 2011-2014 (6). It is predicted that obesity will affect nearly one in two adults by 2030 with higher than 50% prevalence in 29 states, particularly among women (7). Similar statistical predictions exist for pediatric and adolescent age groups. Between the decades of 1980-2012, obesity has more than doubled in children aged 6-11 years (7% to 18%) and quadrupled in adolescents aged 12-19 (5% to 21%) (6). With growing rates of obesity in pediatric and adolescent population, more adolescent girls with weight abnormalities (overweight or obese) are seeking the use of COC to treat several of the gynecological and non-gynecological conditions. Primary care providers and gynecologists often face the concern of weighing the risk of VTE risk with COC use in the setting of obesity.
Although several studies have demonstrated the relationship of VTE risk associated with obesity and COC use, data in adolescent population are limited as most studies include adult women of child-bearing age in their analyses. A case-control study among users of low dose estrogen (< 50 mcg) combined COC, was conducted among women ages 15-44. The adjusted odds ratio (OR) for VTE associated with current COC use was 4.07 (95% CI: 2.77-6.0). The OR was higher for obese women than for non-obese (p=0.01) and was found nearly as doubled in those ≥ 30 kg/m2 compared to ≤ 30 kg/m2 (11). In a systematic review of cardiovascular complications among obese COC users, obese women had 5 to 8 times greater risk for cardiovascular events including myocardial infarction, stroke and VTE compared to non-obese non-COC users and 10 times that of non-obese COC users. Five prospective cohort studies were identified in this systematic review as indirect evidence, all of which supported increased risk for VTE as BMI increased, suggesting a dose-response relationship between BMI and risk for VTE (12). Other studies have similarly confirmed an increased risk for VTE in obese COC users reporting an OR from 5.2 to 7.8 compared with that of obese women who did not use COC (13-15). In a retrospective study of 26 young women (ages 12-21 years) with COC related VTE, 96% of the patients had at least one VTE risk factor and 42% with two or more, with obesity being the most common additional risk factor (50%) (16).
Several hemostatic abnormalities have been observed in obesity such as altered fibrinolysis, increased plasminogen activator inhibitor (PAI-1), increased platelet aggregability through elevations of von Willebrand factor and higher levels of fibrinogen, factors VII and VIII (8-10). Estrogen via nuclear estrogen receptors and progestins (e.g. desogestrel) also affect plasma concentration of clotting factors such as elevated factors II, VII, VIII, X, fibrinogen and decreased antithrombin (17). As a consequence, these coagulation abnormalities can synergistically increase the risk for VTE complications in obese patients on COC therapy. Congenital thrombophilia risk factors such as factor V Leiden have also been demonstrated to increase the absolute risk for thrombosis with COC use (18). However, no underlying thrombophilia risk factors were noted in our patients.
Despite the reported increased risk of VTE in association with COC use and obesity, some groups such as the European Expert Panel recommend contraception “to all women regardless of their weight” considering the need to reduce unintended pregnancy and its associated risk for VTE. The risk of VTE is higher during pregnancy and the postpartum period with an adjusted hazard ratio 16.0 versus 2.2 during COC use (19, 20). Other experts recommend the use of low risk COC with second-generation progestin and lowest estrogen dose in women less than 35 years while women with risk factors for thrombosis such as age > 35 years and obesity, should not use high risk products and primarily consider progestin only COC and be cautious about use of low dose COC (21-23). Second-generation products (norgestrel, levonorgestrel) confer about half the risk for VTE in contrast to third- or fourth-generation products such as desogestrel, gestodene, or drospirenone, cyproterone acetate (21-23). Combined products with 30-40 mcg of estrogen have 20% higher risk for VTE than 20 mcg of estrogen with the same dose and type of progestin (21). Transdermal patches and vaginal rings belong to the high-risk products. Progestin only pills, levonorgestrel intrauterine device and implants do not confer increased risk for VTE (21-23).
The World Health Organization (WHO) and the Center for Disease Control (CDC) provide grade 2 recommendations regarding the use of COC (the advantages generally outweigh the risks) while the United Kingdom Medical Eligibility Criteria (UKMEC) state grade 2 recommendations for those with a BMI <35 kg/m2; grade 3 for those with a BMI 35-39 kg/m2 (the risk usually outweigh the advantages: use not usually recommended unless no alternatives are available and grade 4 for BMI ≥ 40 kg/m2 (the condition represents an unacceptable health risk if the contraceptive method is used; method not to be used) (24-26).
All of our patients had a BMI in the obese category and they encountered VTE complications in the setting of COC use. Although the overall expert opinion is to exercise caution with the use of COC in the setting of obesity, there is need to heighten clinician awareness of the increased risk of VTE complications and choose safer alternatives when prescribing hormonal therapy to adolescents girls with the rising global prevalence of obesity.