Combined hormonal contraceptives merit risk assessment in patients with obesity

In the United States, obesity now affects 40% of reproductive-aged women.¹ Despite lower fecundity of pregnancy-capable people with obesity, the possibility of an unplanned pregnancy remains.² Therefore, an understanding of the unique contraceptive considerations for this population is critical.

We focus this article on considerations for combined hormonal contraceptives (CHCs), which are methods containing both estrogen and progestogen components. Currently available CHC methods in the United States include the combined oral contraceptive (COC) pill, the transdermal patch, and the vaginal ring. Reproductive-aged US women report 80%, 10%, and 8% use of these methods in their lifetime, respectively.³ The primary mechanism of action for all 3 methods is suppression of ovulation through decreased gonadotropin release from the hypothalamus. The contraceptive progestogen component suppresses luteinizing hormone release. The estrogen component suppresses follicle-stimulating hormone release, thereby preventing the formation of a dominant ovarian follicle. The addition of an estrogen component provides improved bleeding control compared with progestin-only methods.

This review will focus on people with obesity who do not have other medical comorbidities. Obesity is defined as a body mass index (BMI) of more than 30 kg/m2, with further subdivision into classes 1, 2, and 3 beyond this cutoff (Figure 1). We review the efficacy of each method, risk of venous thromboembolism (VTE), and weight effects of CHC use in patients with obesity .

What is in a CHC?

All CHCs on the US market are considered low-dose oral contraceptives, meaning they contain less than 50 μg of ethinyl estradiol (EE). Modern-day dose reductions of EE have dramatically reduced the VTE risk seen with historic CHC methods containing more than 50 μg of EE.⁴ Currently, most CHCs available in the United States contain EE. One COC on the US market sold under the name Nexstellis contains estetrol (E4). All other CHCs contain EE. There is a growing body of evidence to support a decreased VTE risk with use of E4 compared with EE.⁵

The progestin (synthetic progestogen) component in available CHCs varies. Some CHC methods have been marketed as reducing the risk of VTE based on the type of progestin used, but the VTE risk between CHC methods with different progestins is negligible. In clinical practice, all available progestins should be considered safe for use. It should be noted that the progestin levonorgestrel (LNG) exhibits weight-dependent dosing. Data from LNG emergency contraception studies have shown that patients with obesity taking LNG have lower serum levels compared with patients with normal weight taking LNG.⁶ In clinical practice, this may translate to concerns about the pregnancy prevention efficacy of CHC methods containing LNG.

US Medical Eligibility Criteria for Contraceptive Use and CHCs

The CDC releases the US Medical Eligibility Criteria for Contraceptive Use to provide guidance on the safe use of contraceptive methods.7 The most recent update from 2020 labels use of all CHC methods in people with obesity as category 2, meaning the advantages of CHC use generally outweigh the theoretical or proven risks (Figure 2).

Prescribing considerations for people with hyperlipidemia, history of bariatric surgery, hypertension, and diabetes mellitus are outside the scope of this review. Given that these medical comorbidities may complicate the health of a person with long-standing obesity, a focused history and physical examination coupled with reference to the medical eligibility remain prudent.

Obesity’s effect on VTE risk

Obesity alone increases the risk of VTE by 2- to 5-fold (Figure 3).^8,9 The leading theory explaining increased VTE risk for patients with obesity is a hyperestrogenic state because of the peripheral conversion of androstenedione to estrone/estradiol in adipose tissue (aromatase reaction). The more adipose tissue (higher BMI), the higher the circulating estrone/estradiol level. Higher circulating estrogens lead to an increased prothrombotic effect on hemostatic pathway.

When obesity is combined with CHC methods, the VTE risk increases further. When considering the risk of VTE with CHC use, it is important to remember that the consequence of withholding contraception may be unintended pregnancy. Therefore, when comparing VTE risk, patients with obesity using CHCs should be compared with pregnant people with obesity (Figure 3). The combined VTE risk of obesity and pregnancy is higher than that of patients with obesity using CHCs.

CHC route of administration

There is a common and incorrect assumption that nonoral (vaginal and transdermal) administration of CHCs lowers the risk of VTE. The risk of VTE with transdermal CHCs is, in fact, higher than that of oral formulations. Currently available vaginal and transdermal contraceptives contain EE, which undergoes significant second-pass hepatic metabolism and therefore acts as a potent activator of the hemostatic pathway even with transdermal or vaginal administration. The dose, not the route, of EE likely plays the most significant role in VTE risk.

COCs

Based on current evidence, it is unclear whether people with obesity have a higher rate of contraceptive failure using COCs. The largest study to examine this question is a 2005 prospective cohort study of 52,000 women that analyzed the failure rates of 2 COCs in patients with and without obesity. Researchers found a statistically significant increase in contraceptive failures with increasing BMI: users with BMI of 35 kg/m2 or higher experienced a failure rate of 3 per 100 women-years compared with 2 per 100 women-years for those with BMI under 35 kg/m2.¹⁰ The pharmacokinetics (PK) of COCs in people with obesity are incompletely understood. Except for LNG, findings from PK studies have not supported the theory that a larger volume of distribution in patients with obesity leads to lower serum concentrations of steroid hormones. Findings from PK studies show changes in half-life and clearance of COCs, with patients with obesity taking longer to reach a steady state compared with patients with normal weight. The clinical significance of these studies as it relates to contraceptive efficacy remains unclear, but the typical 7-day hormone-free interval of COCs can allow for hypothalamic-pituitary-ovarian axis reactivation, particularly for patients with obesity. In patients with obesity taking COCs, continuous COC use or 4-day hormone-free interval pills may have increased efficacy.¹⁰

The absolute risk of VTE in patients with obesity taking COCs remains low.⁸ As Figure 3 shows, VTE risk increases with increasing weight, from 4 to 5 per 100,000 people for individuals with normal weight to 10 to 30 per 100,000 people for individuals with class 1, 2, and 3 obesity. Patients with obesity who take COCs have a VTE risk of 60 to 105 per 100,000 people (depending on obesity class), but pregnant people with obesity have an even higher VTE risk of 100 to 200 per 100,000 people. Understanding this comparison group allows for improved counseling about the relative risk of VTE. There is no evidence that COCs increase rates of stroke or myocardial infarction in patients with obesity.

Many patients cite weight gain as a reason for COC discontinuation, and their personal experiences should be respected. There is no definitive evidence that COCs lead to weight gain. There is also no evidence that patients with obesity are at higher risk of weight gain than individuals with normal weight when initiating COCs.

Contraceptive patch

There are 2 contraceptive patches available on the US market: Xulane (OrthoEvra is an equivalent no longer sold in the United States) and Twirla. Xulane contains EE (35 μg daily) and the progestin norelgestromin. It is designed to be applied weekly for 3 weeks followed by a 7-day patch-free interval. Twirla contains EE (30 μg daily) and the progestin LNG. Twirla is applied in the same fashion as Xulane.

Both patches may have lower efficacy in patients with a weight greater than 90 kg (198 lb). Combined data from 3 contraceptive patch trials showed that 5 of 15 pregnancies were in patients with a weight greater than 90 kg. It should be noted, however, that only 3% of study participants had a weight greater than 90 kg.¹¹ Phase 3 approval data of Twirla found a similar decrease in contraceptive efficacy for users with BMI greater than 30 kg/m2.¹²

There are conflicting data, but findings from small cohort studies suggest a doubling of VTE risk for patients with obesity using the patch compared with those using CHCs of the same oral progestin dose.¹³ Findings from PK studies reveal more overall exposure to estrogen for those using the patch, which may increase VTE risk compared with COCs.^14,15 It is important to keep in mind that rates of VTE remain lower for patients with obesity using the patch than for pregnant patients with obesity.¹⁶

For all patients, weight gain is minimal with the patch. Mean change in body weight is 0.3 kg (0.6 lb) over 13 cycles.¹⁷ No studies focus on weight change specifically for patients with obesity using the patch.

Contraceptive vaginal ring

There are 2 contraceptive vaginal rings (CVRs) available in the United States. NuvaRing contains EE and the progestin etonogestrel. Each NuvaRing is designed for vaginal placement for ²¹ days and removal for a 7-day ring-free period to allow for withdrawal bleeding. Thereafter, a new ring is placed vaginally. Annovera contains EE and the progestin segesterone. Each Annovera ring is designed for vaginal placement for 21 days and removal for a 7-day ring-free period, with replacement of the same ring thereafter. Each Annovera ring can be used for up to 13 cycles.

There are minimal data on the contraceptive efficacy of vaginal rings in patients with obesity. The data that exist support similar efficacy for vaginal ring users with and without obesity. Findings from PK studies in patients using NuvaRing have shown that people with obesity have lower EE levels but no changes to etonogestrel levels compared with patients using NuvaRing with normal weight. This reduction in EE levels may explain why some patients with obesity report a poorer bleeding profile with more days of spotting.¹⁸ However, the progestin—not the estrogen—component of CHCs provides pregnancy protection, and therefore, contraceptive efficacy should not be compromised. CVRs have similar effects on clotting compared with orally dosed EE and therefore have VTE risk similar to that of COCs.¹⁹

As with COCs, CVRs are not associated with weight gain regardless of the starting weight of those using CVRs. Findings from one study demonstrated that fewer women using CVRs compared with those taking COCs experienced weight gain over 1 year (1.7% vs 4.5%).²⁰

Takeaways

• Despite lower lifetime pregnancy rates, people with obesity remain at risk for unplanned pregnancy.
• The VTE risk to a pregnant person with obesity outweighs the VTE increase associated with any CHC (pill, patch, or ring) use.
• Consider prescribing continuous or 24/4 COC pills to people with obesity to increase contraceptive efficacy.
• CHC patches are known to have decreased contraceptive efficacy in patients with obesity, specifically for those with weight greater than 90 kg (198 lb) for Xulane and BMI greater than 30 kg/m2 for Twirla. Patients with obesity can still use the patch after a shared decision-making conversation.
• There is no evidence to support that any of the CHC methods (pill, patch, or ring) increase weight in patients with obesity.

References

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