By Rebecca H. Allen, MD, MPH

Associate 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, and has served as a consultant for Bayer and Pharmanest.

SYNOPSIS: Researchers conducted a systematic review of studies that evaluated the effect of concomitant non-rifamycin antibiotic use on hormonal contraceptive effectiveness. Although data are limited, there was no evidence to support the existence of drug interactions.

SOURCE: Simmons KB, Haddad LB, Nanda K, Curtis KM. Drug interactions between non-rifamycin antibiotics and hormonal contraception: A systematic review. Am J Obstet Gynecol 2017; July 8. pii: S0002-9378(17)30845-1. doi: 10.1016/j.ajog.2017.07.003 [Epub ahead of print].

This systematic review evaluating drug interactions between non-rifamycin antibiotics and hormonal contraception was conducted by the CDC’s Division of Reproductive Health. The review was conducted in support of the most recent update of the U.S. Medical Eligibility Criteria for Contraceptive Use. The review included randomized and non-randomized studies, and all trials contained a control or comparison group. All studies that included women taking any method of hormonal contraception in combination with an oral, intramuscular, or intravenous non-rifamycin antibiotic were included. Clinical outcomes of interest included pregnancy, evidence of ovulation, antibiotic effectiveness, and adverse health effects (breakthrough bleeding, drug side effects). Pharmacokinetic outcomes also were reviewed. The quality of each study was graded with the U.S. Preventive Services Task Force grading system: good (no important limitations, results internally valid), fair (clear limitations but no fatal flaws), or poor (one or more fatal flaws). Meta-analyses could not be conducted because of the heterogeneity of the exposures and outcomes.

Out of 220 possible articles identified, 29 met criteria for inclusion in the review. Four articles were observational studies of pregnancy rates with any antibiotic use. Two of these were case crossover studies, one was a retrospective cohort, and one was a nested case control; the studies were rated as poor to fair in quality. None of these studies, which mostly examined oral contraceptives, showed any effect of antibiotic use on hormonal contraception failure. Next, the authors assessed the 25 trials that evaluated surrogate measures of contraceptive effectiveness (ovulation) and pharmacokinetic outcomes. Penicillins/cephalosporins, tetracyclines, fluoroquinolones, and macrolides were examined when used with oral contraceptives. No differences in ovulation by serum progesterone or ultrasound were observed with ampicillin, doxycycline, temafloxacin, ofloxacin, ciprofloxacin, clarithromycin, roxithromycin, dirithromycin, or metronidazole. Also, there were no significant decreases in any progestin or ethinyl estradiol level caused by antibiotic use in the pharmacokinetic studies. The authors of the pharmacokinetic study evaluated the contraceptive ring and found no interaction with ampicillin or doxycycline.

COMMENTARY

There has been persistent concern that concomitant use of antibiotics with hormonal contraception, especially combined oral contraceptives, could impair efficacy and result in pregnancy.1 Pharmacists and providers often warn patients of this potential. Most of this concern stems from older case reports without controls or patient and provider surveys. Because the typical use failure rate of combined oral contraceptives is 9%,2 a case report of unplanned pregnancy while taking antibiotics does not necessarily mean the antibiotics caused the contraceptive failure. Although rifampin and rifabutin are known inducers of the hepatic enzymes required for contraceptive steroid metabolism, other antibiotics are not. The authors of this review undertook to survey the known literature and assess the evidence to support the assertion that non-rifamycin antibiotics cause hormonal contraception failures.

This systematic review has several strengths, including strict inclusion criteria and the evaluation of a range of clinical and pharmacokinetic outcomes. However, any systematic review is limited by the studies available. In this case, most of the literature in this area is subject to several limitations and biases. For the observational studies, most did not record pill compliance and were flawed regarding how exposure to antibiotics was measured, as well as tracking pregnancy rates. Furthermore, the pharmacokinetic studies were limited by small sample sizes, weakness in ovulation measurement accuracy, lack of randomization, and lack of control for confounders. Pharmacokinetic studies also are limited, as they represent only a surrogate measure of potential contraceptive failure and not a true clinical pregnancy outcome. In addition, minimum contraceptive efficacy thresholds are not yet established for ethinyl estradiol and progestins.3 There were no studies evaluating the contraceptive patch, depot medroxyprogesterone acetate, or the etonogestrel implant. Combined oral contraceptive doses studied included only pills containing 30 or 35 mcg of ethinyl estradiol; therefore, lower-dose pills were not evaluated.

Based on this review, the U.S. Medical Eligibility Criteria for Contraceptive Use provided recommendations for contraceptive use with broad-spectrum antibiotics and other types.4 Although, in general, there is no evidence that broad-spectrum antibiotics interfere with hormonal contraceptive efficacy, there is always the possibility of individual variations in metabolism that could make a patient vulnerable.5 Therefore, if a patient truly believes she had an unplanned pregnancy due to concomitant antibiotic use with hormonal contraceptives, it is reasonable to advise her to use condoms for backup if she uses antibiotics in the future. Similar to other drug-contraception interactions, it is unlikely that depot medroxyprogesterone acetate or intrauterine devices are affected, and patients who are concerned could switch to these methods.

REFERENCES

  1. Dickinson BD, Altman RD, Nielsen NH, et al. Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol 2001;98:853-860.
  2. Trussell J. Contraceptive Efficacy. In: Hatcher RA, Trussell J, Nelson AL, et al. Contraceptive Technology. 20th Revised Edition. New York: Ardent Media; 2010.
  3. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65:1-104.
  4. Cherala G, Edelman A, Dorflinger L, Stanczyk FZ. The elusive minimum threshold concentration of levonorgestrel for contraceptive efficacy. Contraception 2016;94:104-108.
  5. Goldzieher JS, Stanczyk FZ. Oral contraceptives and individual variability of circulating levels of ethinyl estradiol and progestins. Contraception 2008;78:4-9.