By Rebecca H. Allen, MD, MPH
Assistant Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports she is a Nexplanon trainer for Merck, a Liletta trainer for Actavis, and on the advisory board for Bayer, Actavis, and Vermillion.
Synopsis: In this randomized, controlled trial of the effects of combined oral contraceptives on ovarian activity after taking ulipristal acetate, investigators found that some women needed up to 14 days to achieve ovarian quiescence. Therefore, abstinence or backup contraception should be used during that time.
Source: Cameron ST, et al. The effects on ovarian activity of ulipristal acetate when ‘quickstarting’ a combined oral contraceptive pill: A prospective, randomized, double-blind, parallel-arm, placebo-controlled study. Hum Reprod 2015;30:1566-1572.
This double-blind, randomized, controlled trial was conducted in Scotland, Sweden, and the Netherlands between March and August 2012. Healthy female volunteers aged 18 to 35 years, with a body mass index (BMI) of < 30 kg/m2 and regular menstrual cycles, were eligible to participate. Exclusion criteria were use of an intrauterine device or progestin-only method of contraception in the past 3 months, use of depot medroxyprogesterone acetate in the past 12 months, breastfeeding, pregnancy within the past 1 month, or any medications that may interact with study drugs. Women could be on combined oral contraceptives (COCs) prior to the trial. Following menses or withdrawal bleeding, transvaginal ultrasound was performed every 2 to 3 days until the lead ovarian follicle was > 13 mm in mean diameter. Women were then randomized to either ulipristal acetate (UPA) 30 mg or placebo. Women were given 1 packet of combined oral contraceptive pills (30 mcg ethinyl estradiol/150 mcg levonorgestrel) to start taking the same time the following day. The lead follicle was then followed every 2 to 3 days and estradiol/progesterone levels were measured until the follicle was ≤ 13 mm. Women kept daily bleeding diaries, and pill packets were checked for compliance. The time it took for women to reach ovarian quiescence (Hoogland score 1 to 3) was calculated. (See Table 1.)
Table 1 | |||
Hoogland Score1 | Follicular Diameter (mm) | Estradiol (pmol/L) | Progesterone (nmol/L) |
No activity | ≤ 10 | - | - |
Potential activity | > 10 | - | - |
Non-active follicle-like structure | > 13 | ≤ 100 | - |
Active follicle-like structure | > 13 | > 100 | ≤ 5 |
Lutenized unruptured follicle | > 13, persisting | > 100 | > 5 |
Ovulation | > 13, ruptured | > 100 | > 5 |
Overall, 76 women were recruited and received either UPA (39) or placebo (37). There was no difference between the two groups in age or BMI. Approximately three-quarters of the sample had used COCs in the cycle before treatment. There was no difference between the two groups in terms of the proportion reaching ovarian quiescence by day 7 of COC treatment (17 [70.8%] UPA vs 14 [60.9%] placebo). All women in the study reached quiescence by day 14 of COC treatment. There was no difference between the two groups in the number of women who ovulated, with 12 (32%) in the placebo arm and 13 (33%) in the UPA arm.
Commentary
Emergency contraception allows women the chance to prevent pregnancy in case of contraception nonuse or misuse. UPA is a progesterone receptor modulator that is more effective than levonorgestrel emergency contraception, but only available by prescription in the United States.2,3 Because repeated acts of intercourse in the same cycle may lead to pregnancy, it is important to resume a regular contraceptive as soon as possible after using emergency contraception.4 Some women choose to restart combined oral contraceptives immediately after taking UPA. Because UPA is a progesterone receptor modulator, there is a concern that UPA could impact the efficacy of COCs and/or that COCs could impact the efficacy of UPA.
Due to this concern, some experts recommend using abstinence or barrier contraception until the next menses.4 Other experts recommend that a woman can initiate COCs, but she needs to abstain from sexual intercourse or use barrier contraception for 14 days or until her next menses, whichever comes first.5 This is to allow 7 days for the UPA to be metabolized out of the body and 7 days for the COCs to induce ovarian quiescence. Given this uncertainty, the manufacturer funded this study to determine whether UPA interferes with COC’s ability to induce ovarian quiescence.
This study has several strengths, including the randomized design and objective measure of ovarian activity. However, investigators were unable to determine exactly which day ovulation occurred because ultrasounds were performed only every 2 to 3 days. Nevertheless, this study provides important evidence for the expert opinion recommendations that currently exist in the literature. The Centers for Disease Control Selected Practice Recommendations for Contraceptive Use do suggest abstaining from sexual intercourse or using barrier contraception for 14 days after UPA use if hormonal contraception will be initiated immediately. The concern with waiting until the next menses to start hormonal contraception is that UPA may cause shortened cycles, prolonged cycles, or unscheduled bleeding. This may make identification of next menses confusing for women. In addition, the risk of unintended pregnancy if UPA fails and contraception is delayed needs to be taken into consideration.
Unfortunately, this study was not able to address whether COCs will affect the efficacy of UPA. The manufacturer’s U.S. label states (updated March 2015) that because UPA and the progestin component of hormonal contraceptives both bind to the progesterone receptor, using them together could reduce the efficacy of either. After using UPA, they recommend waiting at least 5 days before initiating hormonal contraception.6 More data are still needed regarding this issue. Given that UPA is superior to levonorgestrel emergency contraception, it should be the preferred oral emergency contraceptive, if available and accessible. Otherwise, let’s not forget the copper intrauterine device as an emergency contraceptive that will not interact with hormones and provides both the most effective emergency contraceptive and long-term contraceptive.
REFERENCES
- Hoogland HJ, Skouby SO. Ultrasound evaluation of ovarian activity under oral contraceptives. Contraception 1993;47:583-590.
- Brache V, et al. Ulipristal acetate prevents ovulation more effectively than levonorgestrel: Analysis of pooled data from three randomized trials of emergency contraception regimens. Contraception 2013;88:611-618.
- Glasier AF, et al. Ulipristal acetate versus levonorgestrel for emergency contraception: A randomized non-inferiority trial and meta-analysis. Lancet 2010;375:555-562.
- Raymond EG, Cleland K. Clinical practice. Emergency contraception. N Engl J Med 2015;372:1342-1348.
- Centers for Disease Control and Prevention. U.S. Selected Practice Recommendations for Contraceptive Use, 2013. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr6205a1.htm. Accessed July 27, 2015.
- U.S. Food and Drug Administration. Ella (ulipristal acetate) tablets prescribing information. March 2015. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm306971.htm. Accessed July 27, 2015.