Abstract
The clinical update serves as a brief review of recently published, high-impact, and potentially practice-changing journal articles summarized for our readers. Topics include menopause, sexual dysfunction, breast health, contraception, osteoporosis, and cardiovascular disease. In this clinical update, we selected recent publications relevant to the use of contraceptive methods. We highlight articles on continuation rates of long-acting reversible contraception versus nonlong-acting methods, updated risks of intrauterine devices, use of estrogen-containing contraceptives during anticoagulation for venous thromboembolic events, and the efficacy of oral and emergency contraception in women with elevated body mass index.
Introduction
I
Method Continuation
Diedrich JT et al. Three-year continuation of reversible contraception. Am J Obstet Gynecol 2015;213:662.e1–662.e8.
What we know
In the United States, condoms and combined oral contraceptive pills (COCs) remain the most commonly used contraceptives. Guidelines 1,2 strongly recommend long-acting reversible contraceptive (LARC) methods for most women, yet they remain underutilized. Although there has been an increase in LARC utilization over the past decade, 3 patient and provider concerns about tolerability remain a barrier to more widespread use.
Study results
The authors used data from the Contraceptive CHOICE Project, a prospective observational cohort study of 9256 women who were provided a full range of contraceptive options at no cost. The LARC methods included the 52-mg levonorgestrel (LNG) and copper IUDs and the subdermal implant. Participants were followed with telephone surveys between 2007 and 2011, at 3 and 6 months, then every 6 months for 2–3 years. Women were eligible for the study if they had started their contraceptive by the time of the first 3-month survey. Women who discontinued their contraceptive to attempt conception were excluded. From that group, 4708 participants met the inclusion criteria for this study. Three-year overall continuation rates were 67.2% for LARC users and 31.0% for non-LARC users (p < 0.001); the highest continuation rates were noted among IUD users (69% IUD vs. 56% implant users). When the data were stratified for age, adolescents (aged 14–19 years) had lower continuation rates at 52.6% for LARC and 23.1% for non-LARC methods. The use of depot medroxyprogesterone acetate was also substantially lower than LARC methods; continuation rates at 1, 2, and 3 years were 57.1%, 39.3%, and 33.2%, respectively. Overall, continuation rates in this study at 1, 2, and 3 years were higher with LARC versus non-LARC methods, with IUD use rates at 3 years approaching 70%.
What this changes or adds
This prospective study helps allay concerns about long-term tolerability of LARC methods. There is increasing evidence that IUDs can be inserted by physicians or advanced practice clinicians in nulliparous adolescents with similar success to parous adolescents. 4 LARC methods can be safely offered as a first-line contraceptive option for appropriate patients, including adolescents and nulliparous women; this recommendation has been endorsed in both adult and pediatric society guidelines. 1,2,5
IUD Risks
Heinermann K et al. Risk of uterine perforation with levonorgestrel-releasing and copper intrauterine devices in the European Active Surveillance Study on Intrauterine Devices. Contraception 2015;91: 274–279.
What we know
Although rare, uterine perforation is a known and serious complication associated with IUD use. This has been documented to occur at a rate of 0.3–2.6 per 1000 insertions for LNG-releasing IUDs (LNG-IUD) 6 and 0.3–2.2 for copper IUDs. 7 Updated, larger studies would be helpful given the increasing use of IUDs.
Study results
The European active surveillance study on IUDs was a multinational, prospective, noninterventional cohort study conducted with new and previous users of LNG-IUDs and copper IUDs. This study was performed with the aim of identifying and comparing the incidence of uterine perforation and other serious complications associated with IUD use. Information was collected with the use of a baseline questionnaire completed by study participants before IUD insertion, and a follow-up questionnaire was sent to the patient and provider at 12 months. Recruitment included six European countries via a network of 1230 study centers consisting of specialized clinics, gynecologists, and midwives. Of the 61,448 IUDs placed, 81 uterine perforations were reported, with 61 in the LNG-IUD group and 20 in the copper IUD group. Overall perforation rates were 1.4 versus 1.1 per 1000 insertions in LNG-IUD versus copper groups, respectively. The most significant risk factors associated with perforation were breast feeding at the time of insertion and insertion <36 weeks after the last delivery. Perforation rates in breast-feeding women were 6.3 per 1000 in the LNG-IUD group versus 3.7 in the copper group. Perforation rates in parous, nonbreast-feeding women were very low, 1.0 and 0.5 per 1000 in the LNG-IUD group versus copper group, respectively. Perforations, when present, were not associated with serious illness or injury (e.g., bowel/bladder injury, septicemia, or peritonitis).
What this changes or adds
Reducing unintended pregnancy rates continues to be a challenge, and one part of the solution is to increase the use of LARC methods as their effectiveness is not dependent on the user, and satisfaction and continuation rates are higher than with non-LARC methods. This large study reinforces the low risk of perforation and other complications associated with IUD use.
Estrogen Use During Anticoagulation
Martinelli I et al. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood 2016;127: 1417–1425.
What we know
Current CDC guidelines recommend that combined hormonal contraceptives (CHCs) be avoided during VTE treatment, 1 although these guidelines contrast with other recommendations 8 that indicate select women may continue hormonal therapy while on anticoagulation if there is a strong clinical indication, such as menorrhagia. Little is known, however, about the actual risk for recurrent VTEs and abnormal uterine bleeding (AUB) in the setting of concomitant hormone and anticoagulant therapy use.
Study results
The authors conducted a post-hoc analysis of data from the EINSTEIN DVT and PE trials to compare the incidence of recurrent VTEs and AUB during anticoagulation among women who were either on or off hormonal therapy, including CHCs. Among 1888 women (age <60) with acute symptomatic VTEs who were randomized to treatment with either oral rivaroxaban or subcutaneous enoxaparin (followed by vitamin K antagonist therapy), 475 took concurrent hormonal therapy and 1413 did not. Women on hormonal therapy, as compared with those not using hormones, were younger and less likely to have a history of VTE, active cancer, or anemia. At the end of 1 year, there were no significant differences in the incidence of recurrent VTE or AUB between users and nonusers of hormonal therapy (recurrent VTE: 3.7% vs. 4.7% per year, adjusted hazard ratio [HR] 0.56, 95% CI 0.23–1.39; AUB: 22.5% vs. 21.4% per year, adjusted HR 1.02, 95% CI 0.66–1.57). In the subgroup of women using ethinyl estradiol (such as found in CHCs), as opposed to menopause-related estrogen formulations, the incidences of recurrent VTE and AUB were 4.0% (95%CI 1.1–10.2) and 31.3% (95% CI 20.7–45.0), respectively. Among women using the LNG-IUD, there were no recurrent VTE; the incidence of AUB was 14.3% per year.
What this changes or adds
Although CHCs have been shown to increase the likelihood of both arterial and venous thrombotic events, a recent Cochrane Review suggests that the risk for arterial events (cerebrovascular and myocardial infarctions) may be lower than previously thought. 9 The results of this post hoc analysis suggest that women who use hormonal therapy, including CHCs, while receiving therapeutic anticoagulation for acute VTEs, are not at higher risk for recurrent VTEs. Although the findings of this study are limited by its post hoc design and the inclusion of women who were receiving hormonal therapy for menopausal management (in contrast to contraception), subgroup analyses indicate low rates of VTEs among users of CHCs. The results from this study may prompt providers to offer a wider range of contraceptive options to women receiving anticoagulation, especially when minimizing AUB and maintaining noncontraceptive benefits 10 are a priority.
Obesity and Hormonal Contraception Efficacy
Yamazaki M et al. Effect of obesity on the effectiveness of hormonal contraceptives: An individual participant data meta-analysis. Contraception 2015;92: 445–452.
What we know
Obesity alters the pharmacokinetics and pharmacodynamics of COCs, resulting in lower concentrations of ethinyl estradiol and potentially less suppression of the hypothalamic-pituitary-ovarian axis. 11 However, data from a recent systematic review, 12 as well as the Contraceptive Choice Project, 13 indicate that COCs and other CHCs are equally effective among normal weight and obese individuals (BMI ≥30 kg/m2).
Study results
The authors conducted a meta-analysis of seven phase III clinical trials to compare COC efficacy among nonobese and obese women (pooled n = 11,317 and 2707, respectively). Obesity was defined as a BMI ≥30 kg/m2. Trials included were generally multicenter, open label, and did not have a comparison group. For each trial, investigators calculated the Pearl index (PI), which is the number of unintended pregnancies per 100 woman years of COC exposure. Between the individual trials, the PIs varied between 2.05 and 5.08 for obese women as compared with between 1.84 and 3.80 for nonobese women. Although the results from the individual trials did not demonstrate a significant difference between the different BMI groups, the pooled incidence rate ratio (IRR) suggested that obese women were more likely than nonobese women to experience pregnancy while using COC (IRR 1.37, 95% CI 1.02–1.84). Similarly, obese women were more likely to experience pregnancy over 13 cycles of COC use (HR 1.44, CI 1.06–1.95).
What this changes or adds
The data from this study add to the controversy regarding the contraceptive efficacy of COCs among obese women. The strength of this study is that individual participant data were used from various new drug applications submitted to the Food and Drug Administration. However, the authors acknowledge that they could not account for several factors that might have affected their results, including selection bias in the individual studies. Until additional studies are available, women at high risk for unintended pregnancy should be offered LARC methods. Women who prefer to use CHCs should consider shortening or eliminating the placebo cycle, which may prevent ovulation more reliably. 14
Obesity and EC Efficacy
Kapp N et al. Effect of body weight and BMI on the efficacy of levonorgestrel emergency contraception. Contraception 2015;91:97–104.
What we know
A 2011 meta-analysis of two randomized controlled trials showed that the risk of unintended pregnancy was more than three times higher in obese women taking oral EC than those with a normal BMI (<25 kg/m2). 15 Pregnancy risk was noted to be significantly higher for obese women taking LNG EC than those taking ulipristal acetate (UPA).
Study results
Efficacy data from two multicenter, randomized controlled trials that included an LNG comparison group during UPA EC development were pooled to assess the effect of weight and BMI on pregnancy rates. The analysis included 1731 women using LNG EC, among whom there were 38 pregnancies. Pregnancy rates increased sharply for women who used LNG EC if they weighed between 70 and 80 kg. The pregnancy rate after LNG EC use according to weight categories was 0.9% in women weighing <55 kg, 1.3% for those weighing 55–65 kg, 1.4% for those weighing 65–75 kg, 6.4% for those weighing 75–85 kg, and 5.7% for those weighing ≥85 kg. BMI was found to have a similar relationship with pregnancy rates as body weight, with increased risk seen around 26 kg/m2. However, BMI did not modify the pregnancy rates beyond that of weight alone. The pregnancy rates after LNG EC use based on BMI categories were 1.61% in women with a BMI of <20 kg/m2, 1.26% in those with a BMI of 20–25 kg/m2, 2.45% in those with a BMI of 25–30 kg/m2, 6.71% in those with a BMI of 30–35 kg/m2, and 4.30% in those with a BMI of ≥35 kg/m2.
What this changes or adds
The more effective forms of EC, UPA, and the copper IUD can only be obtained via a provider. Although LNG EC is available over-the-counter without a prescription, it is not the preferred method in women at highest risk of pregnancy, including obese women. Lack of awareness and underutilization of the most effective EC methods by both primary care and reproductive providers have previously been demonstrated. 16 The copper IUD is the most effective method of EC and has the advantage of providing highly effective and convenient long-term contraception. Updated guidelines from the American College of Obstetrics and Gynecology are a helpful resource that provides reassurance about mechanism of action and safety, as well as practical tips, such as the safety of repeated EC use during a single menstrual cycle. 17 However, if the most effective EC methods (e.g., UPA and copper IUD) are unavailable, obese patients should not be discouraged from using LNG EC for fear of decreased efficacy, especially given its established safety profile. 17