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.