Update on Contraception

Abstract

Introduction

The Clinical Update series is intended to help busy clinicians stay current with important and potentially practice changing articles that have been published on topics pertinent to the care of women. In this update on contraception, we have chosen to review studies on emergency contraception (EC) dosing, thrombosis risks with various progestogens, use of depot medroxyprogesterone acetate (DMPA) to treat leiomyoma, as well as interactions between topiramate and etonogestrel serum levels. The role of hormonal contraception in preventing ectopic pregnancies and reducing ovarian cancer risk in BRCA mutation carriers is also reviewed.

Double Dosing Levonorgestrel-Based EC

Edelman AB, et al. Double dosing levonorgestrel-based emergency contraception for individuals with obesity: a randomized controlled trial. Obstet Gynecol. 2022;140(1):48–54.

What We Know

EC is the last line of defense against unintended pregnancy following contraceptive failure or unprotected intercourse, but it is not consistently effective. Both oral levonorgestrel and ulipristal acetate EC pills can reduce the risk of unintended pregnancy by almost 90% by inhibiting or delaying ovulation.^1,2 However, multiple factors impact failure risk, including body mass index (BMI). One study demonstrated a fourfold increase in levonorgestrel emergency contraception (LNG-EC) failure in patients with BMI >30 and a twofold increase among those with BMI 25–29.9 kg/m.^2,3 The typical oral LNG-EC dose is 1.5 mg and requires a 0.2 pg/mL LNG concentration for ovulation suppression.⁴ Individuals who are obese can reach only half the effective pharmacokinetic dose compared to those with normal BMI, increasing the risk for failure.^5,6 A previous study showed that doubling the LNG dose from 1.5 to 3-mg in individuals with obesity approximated drug serum levels similar to those with normal BMI,⁶ yet no studies have evaluated the clinical efficacy of doubling the LNG-EC dose.

Study Results

This randomized controlled study enrolled 70 reproductive-aged women with BMI >30 kg/m² and regular menstrual cycles (median age 28 years and BMI 38 kg/m²). Participants were confirmed to be ovulatory via serum luteal progesterone level >3 ng/mL and had laboratory and ultrasound monitoring of dominant follicle production and subsequent rupture. LNG 1.5 or 3 mg (double dose) was given to participants who had daily monitoring for up to 7 days. There were no differences in follicle rupture post-LNG dosing between those who took 1.5 or 3 mg doses. About 50% of participants from each group reached 5 days or more without evidence of a ruptured follicle, with no difference between the groups for follicle rupture before 5 days.

What This Changes

This study showed that doubling the LNG-EC dose was not effective in improving rates of ovulation delay among women with obesity. In contrast, ulipristal acetate serum concentrations are not impacted by BMI, and this oral EC method has twice the effectiveness of LNG-EC.⁵ The most effective EC method is the copper intrauterine device (IUD), with a recent randomized noninferiority trial suggesting that the 52 mg LNG IUD is similar in effectiveness to the copper IUD.⁷ Thus, for women with obesity who wish to prevent pregnancy, the most effective EC methods, including oral ulipristal acetate, copper IUD, or LNG IUD, should be offered first.

Progestogens and Venous Thromboembolism Risk

Cockrum RH, et al. Association of progestogens and venous thromboembolism among women of reproductive age. Obstet Gynecol. 2022;140(3):477–487.

What We Know

Venous thromboembolism (VTE) is an umbrella term that includes deep venous thrombosis and pulmonary embolism. It occurs in one to two individuals per 1,000 annually, with 300,000–600,000 events in the United States yearly.⁸ Most of the available evidence shows that progestin only contraceptives do not significantly increase VTE risk; however, certain higher dose progestogens (commonly used to treat abnormal bleeding or endometriosis) have been associated with increased thrombosis risk.^9,10 For example, the metabolism of oral norethindrone acetate (NETA) used in doses of 5–10 versus 20–40 mg/day results in serum ethinyl estradiol levels equivalent to those seen with a <15 mcg versus a 30–50 mcg contraceptive pill, respectively.^11,12 A 3.6-fold increased odds of VTE have been shown in DMPA users based on observational data with significant limitations.¹³ Further clarification of VTE risks associated with different progestogens is needed.

Study Results

Cockrum et al. performed a matched case–control study of a U.S. national database of private insurance claims (IBM MarketScan), assessing the use of seven progestogens and acute VTE incidence among reproductive-aged women aged 15–49 years. They excluded women with VTE related to pregnancy and those with chronic VTE (i.e., those with an anticoagulation prescription before the thrombosis episode). During the study period 2010 through 2018, the 21,405 identified women in the case group were matched 1:5 to the control group by birth year and index VTE date. The progestogens included oral medroxyprogesterone, norethindrone, NETA, progesterone, DMPA injection, etonogestrel implant, and LNG-IUDs. Doses were categorized as high if the average daily dose was at least double the standard daily dose of each oral progestogen. A conditional logistic regression model was used to calculate odds ratios and adjusted for 16 VTE risk factors. Of the study population, nearly 60% were aged 40–49 years at the time of the VTE diagnosis.

Compared to nonusers, higher dose progestogens (frequently used to treat medical conditions as opposed to contraceptive use) had significantly increased adjusted odds of VTE (DMPA: adjusted odds ratio [aOR] 2.37, 99% confidence interval [CI] 1.95–2.88; oral medroxyprogesterone acetate: aOR 1.98, 99% CI 1.41–2.80; and NETA: aOR 3.00, 99% CI 1.96–4.59) compared to decreased adjusted odds of VTE for typical contraceptive dose of norethindrone (aOR 0.58, 99% CI 0.44–0.77). The use of the other progestogens did not significantly differ from nonprogestogen users. Although limited by the small sample size and widened CIs, a dose–response association with VTE was observed with NETA and oral medroxyprogesterone acetate (higher risks with doses of ≥10 and 20 mg/day, respectively). As for the chronicity model of progestogen exposure, findings showed increased odds for VTE within the first year of use and decreased odds with continued use. This study had several limitations related to the observational study design, including the fact that 35.6% of inpatient VTE diagnoses did not have an accompanying anticoagulation prescription, which may have led to misclassification bias.

What This Changes

The Centers for Disease Control US Medical Eligibility Criteria (CDC MEC) guidelines note that all progestin-only contraceptive methods can be used in individuals who are at risk for thrombosis (or have a history of VTE). Most progestin-only methods are category 1 (no limitations), while DMPA is category 2 (benefits typically outweigh risks).¹⁴ These findings do not alter these guideline recommendations and provide reassurance regarding the safety of long-acting methods such as hormonal IUDs and the progestin implant. In women at high risk of thrombosis, other progestin-only options outside of DMPA may be preferred for contraception (and perhaps norethindrone can decrease risk). Higher doses of oral medroxyprogesterone acetate and NETA used for therapeutic purposes may have prothrombotic effects, and these risks should be considered with shared decision-making.

DMPA Use to Treat Uterine Leiomyomas

Harmon QE, et al. Depot medroxyprogesterone acetate use and the development and progression of uterine leiomyoma. Obstet Gynecol. 2022;139(5):797–807.

What We Know

Nearly 80% of women will develop uterine leiomyomas, nonmalignant tumors of the myometrium, within their lifetime. These tumors can cause bothersome symptoms such as heavy menstrual bleeding, anemia, and pelvic pain, and are the primary benign indication for hysterectomy in the United States and internationally. Women who choose medical or surgical treatments risk unfavorable outcomes such as infertility or spontaneous return of leiomyomas, with few modifiable risk factors for leiomyomas established. Prior observational studies have suggested that DMPA may decrease leiomyoma growth but have had several limitations.^15
–17 Because a direct effect of DMPA benefits in the treatment of leiomyoma growth has not been demonstrated, prospective studies are needed.

Study Results

The Study of Environment, Lifestyle & Fibroids is a prospective cohort study assessing factors related to both leiomyoma incidence and growth. The study enrolled 1,693 self-identified premenopausal Black women aged 23–35 years without a diagnosis of leiomyomas or hysterectomy between 2010 and 2018. Participants completed four clinic visits at 20-month intervals, where the last use of DMPA was obtained from a questionnaire survey at every visit. The first visit with an observed leiomyoma defined the leiomyoma incidence among women without leiomyoma at enrollment. Cox models were used to assess DMPA associations, with leiomyoma growth calculated as a change in log volume for leiomyomas matched at successive visits and modeled using linear mixed models accounting for clustered data. A Poisson regression model was used to define leiomyoma shrinkage over subsequent visits.

Of the participants, mean age was 29 ± 3.4 years, most had some college education, and close to a quarter had a BMI ≥40 kg/m². Close to half (42.9%) had previously used DMPA, although the groups of prior users and never users were noted to be overall similar. Fewer leiomyomas developed in participants with at least 2 years of DMPA exposure (5.2%) compared with never users (10.7%), with an adjusted hazard ratio (HR) of 0.6 (95% CI 0.4–1.0). Individuals who ever used DMPA had a modest decrease in leiomyoma growth every 18 months. In contrast, never users experienced an average increase of leiomyoma growth of 72.8% per 18 months (95% CI 55.5%–92.1%). Those who ever used DMPA had better leiomyoma loss (i.e., slower growth or shrinkage) than never users (29.3% vs. 21.6%). In addition, participants with recent use of DMPA within 2 years significantly decreased leiomyoma growth by 42.0% (95% CI −51.4 to −30.7). Participants who used DMPA within the prior 2–4 years had significantly reduced leiomyoma size compared to never users.

What This Changes

This study demonstrates that the use of DMPA is a viable treatment for young women with early fibroid. Further research is needed to assess the duration of therapy needed to sustain DMPA effects on leiomyoma incidence and growth and to explore its use as a preventative leiomyoma treatment or to delay symptom onset.

Hormonal Contraceptives and Prevention of Ectopic Pregnancy

Kopp-Kallner H, et al. Method of hormonal contraception and protective effects against ectopic pregnancy. Obstet Gynecol. 2022;139(5):764–770.

What We Know

Ectopic pregnancies are associated with increased maternal morbidity and mortality, accounting for 10%–15% of maternal mortality in North America and roughly 2% of all pregnancies.^18,19 In turn, complications can arise from managing ectopic pregnancies, including lower fertility rates which may warrant infertility treatments. Hormonal contraceptives (HCs) minimize the risk of ectopic pregnancy by attenuating the risk of unintended pregnancy. While IUDs are highly effective at pregnancy prevention, an unintended pregnancy occurring with an IUD may be ectopic in up to 25–50% of cases.²⁰ In the event of method failure, it has been suggested that various progestin-only methods may have different risks for ectopic pregnancy.²¹ How various HC methods impact ectopic pregnancy risk needs to be better defined.

Study Results

This retrospective cohort study reviewed filled prescriptions for HC in the Swedish Prescriber Drug Register between 2005 and 2016 among women aged 15–49 years (median age 27 years with the majority being nulliparous). Copper IUDs and the 19.5 mg LNG-IUD were not evaluated (the latter was not approved in Sweden during the study period). In the cohort of 1,663,242 women, there were 1,915 ectopic pregnancies documented (incidence of 0.28 per 1,000 women years, 95% CI 0.26–0.29). Oral contraceptive pills (OCPs) emerged as the most used contraceptive method in this study population, followed by the 52-mg LNG-IUD (40.1% and 24.7%, respectively). Of the documented ectopic pregnancies, those women with a history of endometriosis had an incidence rate of 0.25 (95% CI 0.12–0.44) per 1,000 woman-years compared to 6.09 (95% CI 4.88–7.50) per 1,000 woman-years for women with a history of previous ectopic pregnancy. None of these women concurrently had a history of ectopic pregnancy and endometriosis.

Among the investigated contraceptive methods, women using a lower-dose 13.5 mg LNG-IUD had the highest risk for ectopic pregnancy, with an incidence rate of 2.76 (95% CI 2.26–3.35) per 1,000 woman-years. The 52-mg LNG IUD had an incidence rate of 0.30 (95% CI 0.28– 0.33) per 1,000 woman-years. Data supported that combination HCs offered a more protective effect than progestin-only options except for injectable DMPA, which also had a lower incidence rate for ectopic pregnancy. OCPs had an incidence rate of 0.20 (95% CI 0.19–0.22) per 1,000 woman-years; etonogestrel implants, 0.31 (95% CI 0.26–0.37) per 1,000 woman-years; and injectable DMPA, 0.06 (95% CI 0.70–0.93). Cox regression models adjusted for age, history of ectopic pregnancy, and endometriosis showed that the history of previous ectopic pregnancy, age younger than 40 years, and use of 13.5-mg LNG IUD had the higher predicted risk for ectopic pregnancy, with the latter two factors having the highest predictive risk.

What This Changes

The best way to prevent ectopic pregnancy is to prevent pregnancy. Thus, highly effective contraceptive options should never be withheld due to fears about ectopic pregnancy, even in those with a prior history. Those at high risk of ectopic pregnancy should be counseled that DMPA, OCPs, and etonogestrel implants (methods which suppress ovulation) will decrease the risk of ectopic pregnancy more effectively than the use of lowest dose LNG-IUDs.

Effect of Topiramate on Serum Etonogestrel Concentrations

Lazorwitz et al. Effect of topiramate on serum etonogestrel concentrations among contraceptive implant users. Obstet Gynecol. 2022;139(4):579–587.

What We Know

In those with a history of seizure disorder, antiepileptic medications can have teratogenic effects, thus highly effective methods of contraception are recommended, with the CDC MEC recommendations suggesting IUDs, DMPA, and the etonogestrel implant as the methods of choice.¹⁴ Many antiepileptic drugs cause strong cytochrome P-450 3A pharmacokinetic effects, reducing serum contraceptive hormonal levels.²² The teratogenic effects of topiramate include low birth weight and craniofacial structural malformations. This medication is also commonly used in reproductive aged women for a variety of indications outside of seizure control, including weight loss and headache prevention. Although carbamazepine has been shown to significantly decrease serum etonogestrel concentrations among contraceptive implant users,^23,24 limited clinical data exist on the effect of topiramate on cytochrome P-450 activity and its clinical implications.

Study Results

Lazorwitz et al. conducted a prospective, noninferiority study of healthy, reproductive-aged women of median age of 25.3 years (range 18.3–37.2 years) to assess drug–drug interactions between topiramate and etonogestrel when the implant was used continuously for 12–36 months. Of the enrolled 48 participants, 32 completed 3 weeks, 31 completed 4 weeks, and 27 completed all follow-up visits. After obtaining baseline serum etonogestrel concentrations, participants started a 6-week titrated topiramate regimen to standard migraine prophylaxis (100 mg/day) and epilepsy treatment (400 mg/day) doses. Serum etonogestrel concentrations were obtained at 3 weeks (100 mg/day), 4 weeks (200 mg/day), and 6 weeks (400 mg/day) of topiramate treatment. A validated liquid chromatography–mass spectrometry assay was utilized to measure serum etonogestrel concentration and assessed whether the baseline amount decreased by <30%; this cutoff was used as the noninferiority definition because a 30% drop would indicate a decrease to below 90 pg/mL (the etonogestrel serum threshold below which ovulation can occur).

At baseline, the median etonogestrel concentration was 142 pg/mL (range 76.2–771) for participants; 126 pg/mL (range 72.4–585) at 3 weeks; 119 pg/mL (range 65.6–542) at 4 weeks; and 105 pg/mL (46.2–859) at 6 weeks. The median serum etonogestrel dropped from baseline by 10.2% at 3 weeks, 20.1% at 4 weeks, and 21.0% at 6 weeks. The corresponding 95% CI for mean percent change in serum etonogestrel concentration is as follows: (−37.3% +16.9%) at 3 weeks, (−45.4% +5.2%) at 4 weeks, and (−66.8% +24.8%) at 6 weeks. At all three visit timepoints, the 95% CIs for mean percent change in serum etonogestrel concentrations were significant for greater than 30% decrease from baseline. Overall, serum etonogestrel concentration successively decreased with each increment in the topiramate dose. At least 30.8% of participants had serum etonogestrel concentration <90 pg/mL at 6 weeks, excluding one participant with <90 pg/mL at baseline.

What This Changes

Reproductive-aged females should continue to receive counseling on the teratogenicity of topiramate and drug–drug interactions with etonogestrel contraceptive implants. Although topiramate has been deemed a mild enzyme-inducing antiepileptic drug, this study determined that concomitant use of topiramate and etonogestrel implant led to a clinically significant reduction in serum etonogestrel concentrations, particularly at an antiepileptic dose (≥200 mg/day). The migraine regimen for topiramate (100 mg/day) has a lesser effect on etonogestrel concentrations but may still impact bleeding profiles or increase the risk of contraceptive failure (especially in those with lower etonogestrel serum levels at baseline).

Oral Contraceptives and Ovarian Cancer Risk in BRCA Carriers

Schrijver LH, et al. Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study. Am J Obstet Gynecol. 2021;225(1):51.e1–51.e17.

What We Know

BRCA1 and BRCA2 genetic mutations carry a high lifetime predisposition for breast and ovarian cancers. The estimated cumulative risk of ovarian cancer varies from 16% to 68% in BRCA1 mutation carriers and from 11% to 30% in BRCA2 mutation carriers.^25,26 In the general population, ovarian cancer risk has been found to diminish by about 50% with five or more years of OCP use, with benefits lasting up to 15 years after discontinuation.^27
–29 Despite this, there is limited evidence of calculated risk reduction associated with OCP use in mutation carriers due to potential bias and small sample sizes.

Study Results

This international retrospective cohort study investigated ovarian cancer risk associations by analyzing contraceptive data on 3,989 BRCA1 and 2,445 BRCA2 mutation carriers. Women with both BRCA1 and BRCA2 mutations and those born before the year 1920 were excluded. An age-dependent weighted Cox regression model, stratified by study and birth cohort, was used to calculate HRs with analyses restricted to person-years at 5 years before baseline. Carriers diagnosed with ovarian cancer were less likely to use contraceptives (58.6% for BRCA1 and 53.5% for BRCA2) than those carriers unaffected (88.9% for BRCA1 and 80.7% for BRCA2). There was a significant risk reduction (HR, 0.51; 95% CI 0.36–0.71) in those BRCA1 mutation carriers who ever used OCPs, which was stronger with prolonged use, and was noted to persist over 15 years following discontinuation of contraceptive use. For BRCA2 mutation carriers, the trend for the reduced risk associated with OCP use was comparable but not clinically significant (HR, 0.65; 95% CI, 0.35–1.19).

What This Changes

For BRCA1 mutation carriers, the results of this study echo similar findings as with the general population in terms of reduced ovarian cancer risk with OCP use, along with a stronger inverse association with prolonged use. For BRCA2 mutation carriers, the findings did not reach statistical significance, possibly due to the small sample size.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

References

Brache

, Cochon

, Deniaud

, et al. Ulipristal acetate prevents ovulation more effectively than levonorgestrel: Analysis of pooled data from three randomized trials of emergency contraception regimens. Contraception, 2013; 88(5):611–618.

Shen

, Che

, Showell

, et al. Interventions for emergency contraception. Cochrane Database Syst Rev, 2017; 8(8):CD001324.

Glasier

, Cameron

, Blithe

, et al. Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel. Contraception, 2011; 84(4):363–367.

Cherala

, Edelman

, Dorflinger

, et al. The elusive minimum threshold concentration of levonorgestrel for contraceptive efficacy. Contraception, 2016; 94:104–108.

Praditpan

, Hamouie

, Basaraba

, et al. Pharmacokinetics of levonorgestrel and ulipristal acetate emergency contraception in women with normal and obese body mass index. Contraception, 2017; 95: 464–469.

Edelman

, Cherala

, Blue

, et al. Impact of obesity on the pharmacokinetics of levonorgestrel- based emergency contraception: Single and double dosing. Contraception, 2016; 94:52–57.

Turok

, Gero

, Simmons

, et al. Levonorgestrel vs. copper intrauterine devices for emergency contraception. N Engl J Med, 2021; 384(4):335–344.

Ortel

, Neumann

, Ageno

, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: Treatment of deep vein thrombosis and pulmonary embolism. Blood Adv, 2020; 4(19):4693–4738.

Gialeraki

, Valsami

, Pittaras

, et al. Oral contraceptives and HRT risk of thrombosis. Clin Appl Thromb Hemost, 2018; 24(2):217–225.

10.

Tepper

, Whiteman

, Marchbanks

, et al. Progestin-only contraception and thromboembolism: A systematic review. Contraception, 201; 94(6):678–700.

11.

Kuhnz

, Heuner

, Hümpel

, et al. In vivo conversion of norethisterone and norethis- terone acetate to ethinyl estradiol in postmenopausal women. Contraception, 1997; 56:379–385.

12.

Chu

, Zhang

, Gentzschein

, et al. Formation of ethinyl estradiol in women during treatment with norethindrone acetate. J Clin Endocrinol Metab, 2007; 92:2205–2207.

13.

van Hylckama Vlieg

, Helmerhorst

, Rosendaal

. The risk of deep venous thrombosis associated with injectable depot-medroxyprogesterone acetate contraceptives or a levonorgestrel intrauterine device. Arterioscler Thromb Vasc Biol, 2010; 30(11):2297–2300.

14.

Curtis

, Tepper

, Jatlaoui

, et al. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR Recomm Rep, 2016; 65(No. RR-3):1–104.

15.

Harmon

, Baird

. Use of depot medroxyprogesterone acetate and prevalent leiomyoma in young African American women. Hum Reprod, 2015; 30:1499–1504.

16.

Wise

, Palmer

, Harlow

, et al. Reproductive factors, hormonal contraception, and risk of uterine leiomyomata in African-American women: A prospective study. Am J Epidemiol, 2004; 159(2):113–123.

17.

Lumbiganon

, Rugpao

, Phandhu-fung

, et al. Protective effect of depot- medroxyprogesterone acetate on surgically treated uterine leiomyomas: A multicentre case-control study. BJOG, 1996; 103: 909–914.

18.

Lawani

, Anomie

, Ezeonu

. Ectopic pregnancy: A life-threatening gynecological emergency. Int J Womens Health, 2013; 5:515–521.

19.

Mann

, Kreisel

, Llata

, et al. Trends in ectopic pregnancy diagnoses in United States emergency departments, 2006–2013. Matern Child Health J, 2020; 24(2):213–221.

20.

Barnhart

. Clinical practice. Ectopic pregnancy. N Engl J Med, 2009; 361(4):379–387.

21.

Callahan

, Yacobson

, Halpern

, et al. Ectopic pregnancy with use of progestin-only injectables and contraceptive implants: A systematic review. Contraception, 2015; 92:514–522.

22.

Gaffield

, Culwell

, Lee

. The use of hormonal contraception among women taking anticonvulsant therapy. Contraception, 2011; 83:16–29.

23.

Lazorwitz

, Davis

, Swartz

, et al. The effect of carbamazepine on etonogestrel concentrations in contraceptive implant users. Contraception, 2017; 95:571–577.

24.

Lange

, Teal

, Tocce

. Decreased efficacy of an etonogestrel implant in a woman on antiepileptic medications: A case report. J Med Case Rep, 2014; 8:43.

25.

Milne

, Antoniou

. Modifiers of breast and ovarian cancer risks for BRCA1 and BRCA2 mutation carriers. Endocr Relat Cancer, 2016; 23(10):T69–T84.

26.

Kuchenbaecker

, Hopper

, Barnes

, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA, 2017; 317:2402–2416.

27.

Kotsopoulos

, Lubinski

, Gronwald

, et al. Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Int J Cancer, 2015; 137:1136–1146.

28.

Havrilesky

, Moorman

, Lowery

, et al. Oral contraceptive pills as primary prevention for ovarian cancer: A systematic review and meta-analysis. Obstet Gynecol, 2013; 122:139–147.

29.

Kumle

, Weiderpass

, Braaten

, et al. Risk for invasive and borderline epithelial ovarian neoplasias following use of hormonal contraceptives: The Norwegian-Swedish Women's Lifestyle and Health Cohort Study. Br J Cancer, 2004; 90:1386–1391.