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• Interaction of non-enzyme-inducing antibiotics with hormonal contraceptives
  Jeffrey K Aronson, Robin E Ferner
  Published on: 21 May 2021
• Letter to the editor in response to “Analysis of reports of unintended pregnancies associated with the combined use of non-enzyme-inducing antibiotics and hormonal contraceptives”
  Cara E Clure, Aaron Lazorwitz
  Published on: 21 May 2021
• Dr
  Chris Gee
  Published on: 21 May 2021

• Published on: 21 May 2021

  Interaction of non-enzyme-inducing antibiotics with hormonal contraceptives

  • Jeffrey K Aronson, Consultant Physician and Clinical Pharmacologist Centre for Evidence Based Medicine, University of Oxford
  • Other Contributors:
    • Robin E Ferner, Honorary Professor of Clinical Pharmacology

  Drs Clure and Lazorwitz have misunderstood and misinterpreted the Yellow Card data that we adduced to test the null hypothesis that there is no interaction of antibiotics with hormonal contraceptives. Here we reply to their specific comments.

  “The medications in each group are not equivalent and bias the sample” We chose a wide range of medicines in order to minimize this. Clure and Lazorwitz have selected only two examples each from the group of nine control drugs and the group of nine non-enzyme-inducing antibiotics, and assert that the age distribution favours older women in the control group. However, they ignore the fact that the same could be asserted of the enzyme-inducing drugs, some of which are more likely to be used in older women, but had an even bigger effect than the antibiotics.

  “The rates of unintended pregnancy reported … are much lower than expected in general users of oral contraception” This is an important misunderstanding, which we sought to obviate in the paper, by making it clear that the data do not allow calculation of the absolute rates of unintended pregnancies. That is because the reported rates are not rates of unintended pregnancies in women taking hormonal contraceptives, but the frequencies of reports of unintended pregnancies as a proportion of all reports of suspected adverse reactions. It is the ratios of frequencies that are important. In other words, whatever the baseline risk is, the risk is 13 times higher with enzyme i...

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  Drs Clure and Lazorwitz have misunderstood and misinterpreted the Yellow Card data that we adduced to test the null hypothesis that there is no interaction of antibiotics with hormonal contraceptives. Here we reply to their specific comments.

  “The medications in each group are not equivalent and bias the sample” We chose a wide range of medicines in order to minimize this. Clure and Lazorwitz have selected only two examples each from the group of nine control drugs and the group of nine non-enzyme-inducing antibiotics, and assert that the age distribution favours older women in the control group. However, they ignore the fact that the same could be asserted of the enzyme-inducing drugs, some of which are more likely to be used in older women, but had an even bigger effect than the antibiotics.

  “The rates of unintended pregnancy reported … are much lower than expected in general users of oral contraception” This is an important misunderstanding, which we sought to obviate in the paper, by making it clear that the data do not allow calculation of the absolute rates of unintended pregnancies. That is because the reported rates are not rates of unintended pregnancies in women taking hormonal contraceptives, but the frequencies of reports of unintended pregnancies as a proportion of all reports of suspected adverse reactions. It is the ratios of frequencies that are important. In other words, whatever the baseline risk is, the risk is 13 times higher with enzyme inducers and seven times higher with non-enzyme inducing antibiotics. Because of the possibility of reporting bias the true ratios are probably lower, but unlikely to approach one, in view of the positive control results.

  We included a group of enzyme-inducing drugs as a positive control, because it is known that there is an increased risk of an unintended pregnancy if a woman taking a hormonal contraceptive also takes an enzyme-inducing drug. Thus, the Yellow Card data confirm the signal; this shows that analysis of the database is capable of revealing a known interaction. We also included fetal malformations as an outcome, since some of the enzyme-inducing drugs are known to be teratogenic. Again, the database revealed the known signal, even though not all of the enzyme inducers have been associated with teratogenicity, and the size of the signal associated with those that have is therefore probably greater than the data suggest. Further support for the usefulness of the database comes from the inclusion of negative control outcomes (cardiac arrhythmias and headache), which would not be expected to yield a signal, and which did not.

  “Pharmacologically, the progestin component of combined oral contraceptives provides the main contraceptive effect” The estrogenic component in a formulation also contributes to inhibition of ovulation, by an action on FSH. This point in fact strengthens the observation that this interaction is likely to be experienced by only a subset of women, those in whom a perturbation of the amount of unbound estrogen to which they are exposed is enough to make a difference between effective and ineffective contraception.

  “it is important to not create false concern” We believe that it is more important that women should not be advised that the interaction does not exist, thus potentially exposing them to the risk of an unintended pregnancy. Women should be informed about the possibility of an interaction and be empowered to decide for themselves what to do about their contraceptive practices during short courses of antibiotics. During longer courses of antibiotics (more than 3–6 weeks), it is likely that the intestinal bacteria become resistant to the effects of commonly used antibiotics [1] and that the risk of an unintended pregnancy is much less, assuming that the mechanism is mediated by an effect on gut bacteria. However, we have no data to support advice in such cases, and that is a question that could be usefully researched.

  We expect that others will find reasons for denying the existence of this interaction. However, UK Summaries of Product Characteristics (“labels”) continue to warn about it [2,3,4] and even those who have not found confirmatory evidence in formal studies have acknowledged, for example, that women “should be advised that this antibiotic/OC controversy exists” [5].

  References
  1. Zlitni, Bishara A, Moss EL, Tkachenko E, Kang JB, Culver RN, Andermann TM, Weng Z, Wood C, Handy C, Ji HP, Batzoglou S, Bhatt AS. Strain-resolved microbiome sequencing reveals mobile elements that drive bacterial competition on a clinical timescale. Genome Med 2020; 12: 50.
  2. Flamingo Pharma. Amoxicillin 500 mg capsules. https://www.medicines.org.uk/emc/product/11312/smpc.
  3. Intrapharma Laboratories Ltd. Oxytetracycline 250 mg tablets. https://www.medicines.org.uk/emc/product/ 4175/smpc.
  4. Aspen. Co-trimoxazole 80/400 mg tablets. https://www.medicines.org.uk/emc/product/ 6999/smpc.
  5. Helms SE, Bredle DL, Zajic J, Jarjoura D, Brodell RT, Krishnarao I. Oral contraceptive failure and oral antibiotics. J Am Acad Dermatol 1997; 36(5 Pt 1): 705-10.

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  Conflict of Interest:
  None declared.

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• Published on: 21 May 2021

  Letter to the editor in response to “Analysis of reports of unintended pregnancies associated with the combined use of non-enzyme-inducing antibiotics and hormonal contraceptives”

  • Cara E Clure, Family Planning Fellow, Ob/Gyn University of Colorado
  • Other Contributors:
    • Aaron Lazorwitz, Assistant Professor, Ob/Gyn-Family Planning

  First available online on August 18, 2020 in BMJ Evidence-Based Medicine, Aronson and Ferner (1) concluded that women using hormonal contraceptives cannot rely on their contraceptive method if they take a short course of non-enzyme inducing antibiotics based on Yellow Card reports to the UK’s Medicines and Healthcare products Regulatory Agency.
  We believe that there are fundamental scientific issues and limitations with this study not adequately addressed by the authors. First, Yellow Card reports require provider reporting of an unintended pregnancy, which the authors acknowledge are subject to reporting bias. As the authors also acknowledge, many healthcare providers suspect there are drug-drug interactions between hormonal contraception and all antibiotics, despite the lack of definitive evidence (1). Therefore, there already exists a bias among providers that they would suspect and report an unintended pregnancy attributed to a drug-drug interaction among women taking antibiotics. The medications in each group are also not equivalent and bias the sample. For example, in the antibiotic group, metronidazole and nitrofurantoin are more commonly used in younger reproductive-aged and sexually active women (2,3), the population at highest risk of unintended pregnancies (4). In comparison, the control group includes such medications as propranolol and theophylline, which are used for treatment of cardiac and respiratory conditions more common among older women (5,6), wi...

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  First available online on August 18, 2020 in BMJ Evidence-Based Medicine, Aronson and Ferner (1) concluded that women using hormonal contraceptives cannot rely on their contraceptive method if they take a short course of non-enzyme inducing antibiotics based on Yellow Card reports to the UK’s Medicines and Healthcare products Regulatory Agency.
  We believe that there are fundamental scientific issues and limitations with this study not adequately addressed by the authors. First, Yellow Card reports require provider reporting of an unintended pregnancy, which the authors acknowledge are subject to reporting bias. As the authors also acknowledge, many healthcare providers suspect there are drug-drug interactions between hormonal contraception and all antibiotics, despite the lack of definitive evidence (1). Therefore, there already exists a bias among providers that they would suspect and report an unintended pregnancy attributed to a drug-drug interaction among women taking antibiotics. The medications in each group are also not equivalent and bias the sample. For example, in the antibiotic group, metronidazole and nitrofurantoin are more commonly used in younger reproductive-aged and sexually active women (2,3), the population at highest risk of unintended pregnancies (4). In comparison, the control group includes such medications as propranolol and theophylline, which are used for treatment of cardiac and respiratory conditions more common among older women (5,6), with known decreased fertility (7). Without any summary demographic information about these populations (e.g. age, socioeconomic status), we cannot assume that the control and exposure groups have equivalent baseline risk for unintended pregnancies.
  The rates of unintended pregnancy reported in each of the groups (0.009% in controls, 0.062% in the antibiotic group, 0.12% in the enzyme-inducing group) (1) are also much lower than expected in general users of oral contraception. The failure rate with typical use of oral contraceptives is approximately 7% and 0.3% with perfect use (8). While the authors note that absolute risks cannot be calculated from this data, caution needs to be taken interpreting data that is vastly disparate from known actual use data. Lastly, the article proposes mechanisms to explain the potential interaction between oral contraceptives and antibiotics focusing on how drug interactions affect estrogen levels in oral contraceptives. Pharmacologically, the progestin component of combined oral contraceptives provides the main contraceptive effect (8). Furthermore, progestins do not rely on enterohepatic recirculation like estrogens, and thus antibiotic-induced gastrointestinal changes would not affect the efficacy of these progestins (9,10).
  Without scientifically rigorous data, it is important to not create false concern for women taking oral contraceptives and prescribed non-enzyme inducing antibiotics. While we agree that further research is needed in this area, there are significant limitations to this study that greatly reduce its applicability to actual clinical practice.

  References:
  1.) Aronson JK, Ferner RE. Analysis of reports of unintended pregnancies associated with the combined use of non-enzyme-inducing antibiotics and hormonal contraceptives. BMJ Evidence-Based Medicine Published Online First: 18 August 2020. Doi: 10.1136/bmjebm-2020-111363.
  2.) Tinker SC, Broussard CS, Frey MT, Gilboa SM. Prevalence of Prescription Medication Use among Non-Pregnant Women of Childbearing Age and Pregnancy Women in the United States – NHANES, 1999-2006. Maternal and Child Health Journal 2015; 19(5): 1097-1106.
  3.) Palmsten K, Hernandez-Diaz S, Chambers CD, Mogun H, Lai S, Gilmer TP, Huybrechts KF. The Most Commonly Dispensed Prescription Medications Among Pregnant Women Enrolled in the United States Medicaid Program. Obstetrics and Gynecology 2015; 126(3): 465-473.
  4.) Unintended Pregnancy in the United States. Guttmacher Institute, 2019. https://www.guttmacher.org/fact-sheet/unintended-pregnancy-united-states. Accessed August 28, 2020.
  5.) Martin CB, Hales CM, Qiuping G, Ogden CL. Prescription drug use in the United States, 2015-2016. NCHS Data Brief 2019; 334: 1-8.
  6.) Henriksen DP, Davidsen JR, Laursen CB. Nationwide use of theophylline among adults – A 20-year Danish drug utilization study. Respiratory Medicine 2018; 140: 57-62.
  7.) American College of Obstetricians and Gynecologic Practice and Practice Committee. Female age-related fertility decline. Committee Opinion No. 589. Fertility and Sterility 2014; 101(3): 633-634.
  8.) Cwiak C, Edelman A. Combined Oral Contraceptives (COCs). In: Contraceptive Technology, 21st ed, Hatcher RA, Nelson AL, Trussell J, et al. Ayer Company Publishers, Inc., New York 2018.
  9.) Orme ML, Back DJ. Factors affecting the enterohepatic circulation of oral contraceptive steroids. American Journal of Obstetrics and Gynecology 1990; 163(6): 2146-52.
  10.) Elomaa K, Ranta S, Tuominen J, Lahteenmaki P. The possible role of enterohepatic cycling on bioavailability of norethisterone and gestodene in women using combined oral contraceptives. Contraception 2001; 63(1): 13-18.

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  Conflict of Interest:
  None declared.

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• Published on: 21 May 2021

  Dr

  • Chris Gee, GP Harston Surgery

  Might it be helpful to clarify in the title or abstract that the paper relates solely to estrogen containing contraceptives, and essentially the oral versions?

  Conflict of Interest:
  None declared.

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