Clinical Review

Hormonal contraception in women with medical conditions

OBG Manag. 2006 September;18(9):37-49

References

1. Use of Hormonal Contraception in Women With Coexisting Medical Conditions. ACOG Practice Bulletin #73. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2006;107:1453-1472.

2. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

3. Davidson NE, Helzlsouer KJ. Good news about oral contraceptives. N Engl J Med. 2002;346:2078-2079.

4. Milne RL, Knight JA, John EM, et al. Oral contraceptive use and risk of early-onset breast cancer in carriers and non-carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev. 2005;14:350-356.

5. Whittemore AS, Balise RR, Pharoah PD, et al. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 and BRCA2 mutations. Br J Cancer. 2004;91:1911-1915.

6. Narod SA, Risch H, Moslehi R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med. 1998;339:424-428.

7. Ragueneau-Majlessi I, Levy RH, Janik F. Levetiracetam does not alter the pharmacokinetics of an oral contraceptive in healthy women. Epilepsia. 2002;43:697-702.

8. Griffith SG, Dai Y. Effect of zonisamide on the pharmacokinetics and pharmacodynamics of a combination ethinyl estradiol-norethindrone oral contraceptive in healthy women. Clin Ther. 2004;26:2056-2065.

9. McCann MF, Potter LS. Progestin-only oral contraception: a comprehensive review. Contraception. 1994;50(6 suppl 1):S1-S195.

10. Haukkamaa M. Contraception by Norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant treatment. Contraception. 1986;33:559-565.

11. Bounds W, Guillebaud J. Observational series on women using the contraceptive Mirena concurrently with antiepileptic and other enzyme-inducing drugs. J Fam Plann Reprod Health Care. 2002;187:551-555.

12. Mattson RH, Rebar RW. Contraceptive methods for women with neurologic disorders. Am J Obstet Gynecol. 1993;168:2027-2032.

13. Back DJ, Breckenridge AM, Crawford F, et al. The effect of rifampicin on norethisterone pharmacokinetics. Eur J Clin Pharmacol. 1979;15:193-197.

14. Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL. Interaction of St. John’s wort with oral contraceptives: effects on the pharmacokinetics of norethindrone and ethinyl estradiol, ovarian activity, and breakthrough bleeding. Contraception. 2005;71:402-408.

15. Abdollahi M, Cushman M, Rosendaal F. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use. Thromb Haemost. 2003;89:493-498.

16. Zieman M, Guillebaud J, et al. Contraceptive efficacy and cycle control with Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril. 2002;77:S13-S18.

17. Holt VL, Scholes D, Wicklund KG, Cushing-Haugen KL, Daling JR. Body mass index, weight, and oral contraceptive failure risk. Obstet Gynecol. 2005;105:46-52.

18. Anderson FD. Hait H and the Seasonale-301 Study Group. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception. 2003;68:89-96.

19. Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

20. Leiman G. Depo-medroxyprogesterone acetate as a contraceptive agent: its effect on weight and blood pressure. Am J Obstet Gynecol. 1972;114:97-102.

21. Jain J, Jakimiuk AJ, Bode FR, Ross D, Kaunitz AM. Contraceptive efficacy and safety of DMPA-SC. Contraception. 2004;70:269-275.

22. Bermas BL. Oral contraceptives in systemic lupus erythematosus—a tough pill to swallow? N Engl J Med. 2005;353:2602-2604.

23. Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic lupus erythematosus. OC-SELENA Trial. N Engl J Med. 2005;353:2550-2558.

24. Sanchez-Guerrero, Urive AG, Jimenez-Santana L, et al. A trial of contraceptive methods in women with systemic lupus erythematosus. N Engl J Med. 2005;353:2539-2549.

25. Orr-Walker BJ, Evans MC, Ames RW, et al. The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal postmenopausal women. Clin Endocrinol (Oxf). 1998;49:615-618.

26. Petitti DB, Piaggio G, Mehta S, Cravioto MC, Meirik O. Steroid hormone contraception and bone mineral density: a cross-sectional study in an international population. The WHO Study of Hormonal Contraception and Bone Health. Obstet Gynecol. 2000;95:736-744.

27. Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. Injectable hormone contraception and bone density: results from a prospective study [published erratum appears in Epidemiology. 2002;13:749]. Epidemiology. 2002;13:581-587.

28. Scholes D, LaCroix AZ, Ichikawa LE, et al. Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med. 2005;159:139-144.

29. World Health Organization. Medical eligibility criteria for contraceptive use. Annex 1. COCs and antiretroviral therapies. 3rd ed. Geneva: WHO; 2004.

30. Sapire KE. Depo-provera and carbamazapine. Br J Fam Plann. 1990;15:130.-

Dr. Kaunitz has received funding from Barr Laboratories, Berlex, Johnson & Johnson, and the National Institutes of Health. He is a speaker or consultant for the American College of Obstetricians and Gynecologists, the Association of Reproductive Health Professionals, Barr Laboratories, Berlex, Johnson & Johnson, Pfizer, and Procter & Gamble; and holds stock with Noven, Roche, and Sanofi-Aventis.

The bottom line: Women with a family history of breast cancer in general or BRCA1 or BRCA2 mutations more specifically, who have not completed childbearing or who want to avoid prophylactic mastectomy/oophorectomy, can use the Pill to prevent ovarian cancer without increasing their risk of breast cancer.^5,6

2. Concomitant medications

Some drugs decrease steroid levels

Anticonvulsants

OBG Management: Many, perhaps most, women with medical conditions are already taking some kind of medication. What do ObGyns need to know about interactions between hormonal contraceptives and other medications, such as anticonvulsants and antibiotics?

KAUNITZ: We regularly encounter patients who are using anticonvulsants, both older and newer formulations.

Off-label use of anticonvulsants for indications other than seizure disorders (eg, bipolar disease) is increasing.

Levetiracetam and zonisamide. The revised practice bulletin includes pharmacokinetic data on 2 new anticonvulsants—levetiracetam⁷ and zonisamide.⁸ Fortunately, neither appears to reduce contraceptive steroid levels in women who are also taking combination OCs.

Which dosage, which method? Some widely used anticonvulsants do decrease steroid levels (TABLE 1); although some clinicians prescribe OCs containing 50 μg of ethinyl estradiol to offset the reduction, there is no evidence that this strategy is effective. The ObGyn may consider prescribing pills containing 30 to 35 μg of estradiol rather than lower doses, although again, we lack data to support this recommendation.

Another important point: Because serum steroid levels of women using progestin-only OCs and implants are lower than for combination OCs, low-dose progestin-only methods (progestin-only minipills and progestin implants) do not represent by themselves optimal contraceptives for women taking drugs (eg, anticonvulsants) that increase liver enzymes.^9,10

This recommendation does not include the levonorgestrel-releasing intrauterine system. Contraceptive effects remain high with its use, even when anticonvulsants or other liver enzyme-inducing drugs are taken.¹¹

DMPA, a high-dose progestin contraceptive, has not been formally studied in this regard; the efficacy of this injectable contraceptive does not appear to be reduced by concomitant use of enzyme inducers.³⁰ Interestingly enough, DMPA has anticonvulsant effects itself and therefore may represent a particularly attractive contraceptive for women taking anticonvulsants.¹²

TABLE 1

Some anticonvulsants reduce steroid levels in women taking OCs, and some do not

Interaction of anticonvulsants and combination OCs
*Anticonvulsants that decrease* steroid levels in women taking oral contraceptives (OCs)**
Barbiturates (including phenobarbital and primidone)
Carbamazepine and oxcarbazepine
Felbamate
Phenytoin
Topiramate
Vigabatrin
*Anticonvulsants that do not decrease* steroid levels in women taking combination OCs**
Ethosuximide*	Tiagabine^†
Gabapentin^†	Valproic acid
Lamotrigine^†	Zonisamide
Levetiracetam
* No pharmacokinetic data available.
^†Pharmacokinetic study used anticonvulsant dose lower than that used in clinical practice.
Source: American College of Obstetricians and Gynecologists.¹ Reprinted by permission.

Antibiotics

KAUNITZ: As for antibiotics, we have often been taught that many drugs lower the efficacy of combination OCs, but in fact it is not clear that they do.

Rifampin. The only antibiotic for which we have pharmacokinetic evidence of substantially lower steroid levels is rifampin¹³ (although anecdotal reports of OC failure in women taking other antibiotics have been noted). Therefore, any woman who is taking rifampin should be advised that OCs (combination or progestin-only), transdermal or vaginal contraceptives, and hormonal implants are inadequate birth control (TABLE 2).

TABLE 2

Rifampin decreases steroid levels in women taking combination OCs; other anti-infectives do not

Interaction of anti-infective agents and combination OCs
*Anti-infective that decreases* steroid levels in women taking OCs**
Rifampin
*Anti-infectives that do not* decrease steroid levels in women taking OCs**
Ampicillin	Miconazole*
Doxycycline	Quinolone antibiotics
Fluconazole	Tetracycline
Metronidazole
*Vaginal administration does not lower steroid levels in women using the contraceptive vaginal ring.
Source: American College of Obstetricians and Gynecologists.¹ Reprinted by permission.

Antiretrovirals

KAUNITZ: Several small trials suggest that contraceptive steroid levels in OC users may be affected by antiretroviral medications (TABLE 3), but we lack clinical outcome studies.

TABLE 3

Antiretrovirals may affect steroid levels in women taking OCs

Pharmacokinetic interactions between combination OCs and antiretroviral drugs
ANTIRETROVIRAL	CONTRACEPTIVE STEROID LEVELS	ANTIRETROVIRAL LEVELS
PROTEASE INHIBITORS
Nelfinavir	↓	No data
Ritonavir	↓	No data
Lopinavir/ritonavir	↓	No data
Atazanavir	↑	No data
Amprenavir	↑	↓
Indinavir	↑	No data
Saquinavir	No data	No change
NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
Nevirapine	↓	No change
Efavirenz	↑	No change
Delavirdine	?↑	No data
Source: World Health Organization.²⁹ Reprinted by permission.

St. John’s wort

KAUNITZ: Another medication I want to mention is St. John’s wort, an over-the-counter hepatic enzyme inducer that many women take for depression. One clinical trial found elevated progestin and estrogen metabolism in women taking combination OCs and St. John’s wort concomitantly, as well as increased likelihood of breakthrough bleeding and ovulation.

St. John’s wort (300 mg thrice daily) was associated with a 13% to 15% reduction in the dose exposure of combination OCs containing 20 μg of ethinyl estradiol.¹⁴ So it is important to ask about St. John’s wort when counseling a woman about contraception.

St. John’s wort raised progestin and estrogen metabolism and increased breakthrough bleeding and ovulation in women taking OCs