Explaining Contraceptive Risks. Update on Medical Eligibility Criteria for Contraceptive Use

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Hortense Quinn
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1 Beth Kutler FNP

2 Explaining Contraceptive Risks Update on Medical Eligibility Criteria for Contraceptive Use Questions in Contraception Transdermal patch DMPA Drug Interactions IUDs Case Studies While I have no financial disclosures, I will be discussing off-label use of medications

3 Factors in Choosing Contraception Convenience Effectiveness Cost Privacy Partner acceptance Cultural norms Expected side effects Health Risks

5 Explaining Contraceptive Risk Absolute Risk Attributable Risk Relative Risk

6 Absolute Risk The percentage of people in a group who experience a discrete event Number of events experienced Total exposure time of people at risk

7 Example of Absolute Risk The pill scare of 1995 Of 100,000 women using third generation progestins (desogestrel, norgestimate), 30 people developed a VTE (venous thromboembolic event) per year Absolute Risk = 30 per 100,000 women years

8 Attributable Risk The difference in risk between those exposed and those not exposed Reflects extra risk associated with exposure Risk in exposed Risk in unexposed

9 Example of Attributable Risk The absolute risk of VTE in women who took second generation OCs (norgestrel, levonorgestrel) was 15 per 100,000 woman years compared with 30 per 100,00 woman-years in those using third generation OCs. The attributable risk of VTE in women taking third generation OCs is 15 per 100,000 30/100,000-15/100,000= 15/100,000

10 Relative Risk Frequency of the outcome in the exposed group divided by the frequency of the outcome in the unexposed group. Reflects the likelihood of developing an outcome based on an exposure

11 Relative Risk Example (30/100,000) (15 / 100,000) Absolute risk of taking third generation OCs Absolute risk of taking second generation OCs = 2

12 Interpreting RR Relative Risk Interpretation 1.0 No increase in risk of outcome in exposed group compared with unexposed group >1.0 Increased risk of outcome in exposed group <1.0 Decreased risk of outcome in exposed group Women taking 3rd generation OCs had a risk of VTE two times that of women taking second-generation OCs.

13 Estimated Incidence of VTE in Women Group Former Estimates Newer Estimates Reproductive Aged Women 4/100,000 74/100,000 (EURAS Data) Pregnant /postpartum 60/100,00 200/100,000 Women Using COCs 15-30/100,000 drsp 91/100,000 lng 80/100,000 other COC 99/100,000

Even if the relative risk was correctly stated, the absolute risk of VTE is very small (15-99/100,00) Extra risk of dying from a VTE if switching from a 2nd to a 3rd

16 Even if the relative risk was correctly stated, the absolute risk of VTE is very small (15-99/100,00) Extra risk of dying from a VTE if switching from a 2nd to a 3rd generation COC 2 per million = risk of dying from driving for 2 hours If a woman can avoid driving for 2 hours, this counteracts the effect of taking a 3rd generation pill

18 World Health Organization Recommendations Category 1: No Restrictions Category 2: Generally Use (Benefits usually outweigh risk) Category 3: Usually Not Recommended (clinical judgment and continuing access to clinical services are required for use) Category 4: Absolute Contraindication

20 MEC full guidelines and MEC wheel from WHO

21 Migraine With Aura (any age) Cat 4 (I) COC Cat 4 (C) COC Cat 2 (I) POP Cat 2 (C) POP

22 Hypertension Category 3 History of hypertension and blood pressure cannot be evaluated or is controlled and can be evaluated Systolic or diastolic Category 4 Systolic >= 160 or Diastolic >=100

24 Pill/Patch/Ring Contraception Drug Interactions Tegretol Felbatol Nevirapine Trileptal Phenobarbital Dilantin Mysoline Rifabutin Rifampin St. John s Wort Topamax Vigabatrin Griseofulvin Olestin Possibly Ethosuximide Troglitazone

25 Dogterom P, van den Heuvel et al. 2005

26 Surveys of Apparent Oral Contraceptive Failures in Women Taking Oral Antibiotics Dickinson et.al 2001

27 Any contraceptive failure while using antibiotics is more likely related to GI upset associated with antibiotics Missing pills due to increased medication taking demands Confusion regarding effectiveness

28 Discussing Risk The Patch Designed to deliver 20 mcg of EE and 0.15 mg norelgestomin daily In actuality Up to 60 % greater steady state blood levels of EE compared with 35 mcg COC Peak EE blood levels lower than with 35 mcg EE pill Greater total hormone exposure Significance??

29 EE Serum Concentrations Differ by Routes of Administration Mean concentration versus- time curves Fig. 2. Mean EE C-T curves for subjects (ASPE group) treated with NuvaRing (n=8), the transdermal contraceptive patch (n=6) and the COC (n=8). Contraception Van den Heuvel. Volume 72, Issue 3, September 2005, Pages

30 References: van den Heuvel MW, van Bragt AJ, Alnabawy AK, Kaptein MC. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception. 2005;72:

In medical research, the odds ratio is favored for case-control studies and Relative risk is used in randomized controlled trials and cohort studies Jick SS, Kaye JA, Russmann S, Jick H.

31 In medical research, the odds ratio is favored for case-control studies and Relative risk is used in randomized controlled trials and cohort studies Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception. 2006;73: Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol. 2007;109: Ortho Evra [revised prescribing information]. Raritan, NJ: Ortho-McNeil Pharmaceutical, Inc; September 2006.

33 Company and FDA issued warning based on: 2007 Cole et.al 49,048 women-years of exposure RR 2.2 (95% CI ) Significant 2006 Jick et al 58, 752 women-years of exposure RR 1.1 (95% CI )- Neutral 2007 Jick et al Additional 17 mo of data OR 1.1 (95% CI )- No Change 2008 Boston Collaborative Drug Surveillance RR 2 - Not Significant

prescribing practice except to say is not safer than COC.

34 Significance Worst Case RR 2.2 = roughly 40/ 100,00 thrombosis Take home- Risk small enough that most have not changed prescribing practice except to say is not safer than COC. Contraindication to COC= Contraindication to the patch Women with other risk factors for VTE (ie. obesity, smoking, immobilization) should discuss alternative contraceptive options with their healthcare provider.

35 Weight Concerns 3 lb average gain - P/P/R 5 lb cumulatively DMPA Decrease effectiveness patch > 90 Kg (though still better than condoms)- Use BUM- dual always with adolescents regardless No decrease effectiveness with Nuva Ring Implanon- Not studied in greater than 130 % IBW (BMI>30)

36 Body weight and risk of oral contraceptive failure. Holt VL; Cushing-Haugen KL; Daling JR Obstet Gynecol 2002 May;99(5 Pt 1): N= 755 retrospective questionnaire. Women greater than 70.5 kg = RR 1.6 Obese Very low dose OC users = RR 4.5 Suggest that body habitus may affect metabolism sufficiently to compromise contraceptive effectiveness. Consideration of a woman's weight may be an important element of OC prescription. Failures were highest in women >154# who use lower dose formulas

37 Body mass index, weight, and oral contraceptive failure risk. Holt VL; Scholes D; Wicklund KG; Cushing-Haugen KL; Daling JR Obstet Gynecol 2005 Jan;105(1): N= 248 Risk of pregnancy was nearly 60% higher in BMI >27.3 = OR 1.58 Suggest that being overweight may increase the risk of becoming pregnant while using OCs. If causal, this association translates to an additional 2-4 pregnancies per 100 woman-years of use among overweight women, for whom consideration of additional or effective alternative contraceptive methods may be warranted. Follow-up study substantiated overall higher failure rates, did not claim any dosedependent relationship

38 The Role of Body Weight in Oral Contraceptive Failure: Results from the 1995 National Survey of Family Growth. Annals of Epidemiology, Volume 15, Issue 7, Pages L. Brunner, C. Hogue Women with a BMI 30 had a statistically significant increased risk of having an OC failure as compared to women with BMIs of 20 to 24.9 (HR = 1.80, 95% CI, 1.01, 3.20). However, after adjustment for age, marital status, education, poverty, race/ethnicity, parity, and dual method use, this increased risk was attenuated and no longer statistically significant (HR = 1.51, 95% CI, 0.81, 2.82). Increasing body weight was not associated with an increased risk of OC failure in the unadjusted or adjusted models. Retrospective study adjusted for confounding factors= no increased risk.

39 Contraceptive Technology 2007 recommends against routinely prescribing high-dose COC to obese women due to VTE risk. It may be better to decrease or eliminate the pill free interval for heavier women

40 Discussing Risk Depo. And your bones..

41 The Black Box Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk for osteoporotic fracture in later life. Depo-Provera Contraceptive Injection should be used as a longterm birth control method (e.g. longer than 2 years) only if other birth control methods are inadequate. (See WARNINGS.) 11/2004

42 Managing Contraception : Bone Mineral Density and Depo-Provera Women who used DMPA for more than 2 years have significantly reduced bone mineral density (BMD) of lumbar spine and femoral neck. But effect is largely reversible, even after > 4 years of DMPA use, comparable to the effect and reversal seen after lactation [Petitti-2000]. All women using DMPA including teens should to taking in sufficient calcium in diet or be encouraged to take calcium supplements. Also encourage to exercise regularly and avoid smoking. A double-blind randomized controlled study of estrogen supplementation in adolescent girls demonstrated at 24 months of DMPA use an increase of 4.7% in femoral neck bone density in teenagers receiving monthly injections of estradiol cypronate (5 mg) and a decrease of 5.1% in femoral neck bone density in teens provided DMPA and monthly placebo injections of 5 mi normal saline [Cromer-2005]. Bone mass may return after Depo-Provera has been discontinued. Cromer et al indicate that they "cannot conclude that observed bone loss in irreversible until further study is conducted and the relevant data have been obtained." [Cromer-2005]

43 DMPA-IM 150: BMD during/after use in adult women (n=457) In current users, BMD was decreased vs nonusers (mean annual decline: 0.9 percent). Following discontinuation, BMD increased. After 30 months, spine and hip BMD in discontinuers was similar to nonusers. BMD recovery not impacted by duration of DMPA use. * Median duration of use, 11 months (range, months). Scholes, D, LaCroix, AZ, Ichikawa, LE, et al

44 Fig. 1. Mean percentage change from baseline in BMD for subjects treated with DMPA vs. the nonhormonal group (modified ITT population). Results are presented for (A) total hip, (B) lumbar spine, (C) femoral neck and (D) femoral trochanter during up to 5 years (240 weeks) of treatment and up to 2 years (96 weeks) of posttreatment follow-up. The p values are for betweengroup differences at each time point. ap<.05, significant difference between groups. DMPA 150, DMPA (intramuscular injection) group; NH, nonhormonal group. Kaunitz, et al. 2006

46 In July, 2005, the World Health Organization in Geneva released the following statements on Depo-Provera use There should be no restriction on the use of DMPA, including no restriction on duration of use, among women ages 18 to 45 who are otherwise eligible to use the method. Among adolescents (menarche to <18) and women over 45, the advantages of using DMPA generally outweigh the theoretical safety concerns regarding fracture risk. Since data are insufficient to determine if this is the case with long-term use among these age groups, the overall risks and benefits for continuing use of the method should be reconsidered over time with the individual user. These statements, therefore, suggest no change in the 2004 Medical Eligibility Criteria published by the World Health Organization

47 Case Study #1 19 yo sophomore with a history of severe dysmenorrhea and iron deficiency anemia. She gets bad headaches that make her nauseous and photophobic- usually with her periods. She denies any warning sign of her headaches or symptoms such as visual changes or facial numbness. She is requesting contraception. What are her contraceptive options?

48 #2 21 year old Hispanic senior with a history of an eating disorder. She remains oligomenorrheic with a BMI Of 17. Her mother is not aware she is sexually active and your patient does not want her mother to know otherwise. What are her contraceptive options?

49 #3 24 year old female with a BMI of 35. Her menses are regular and she does not want to get pregnant. She is asking what the most effective, economical method is for her. What are her contraceptive options??

50 #4 18 year old Junior who had both Chlamydia and an ectopic pregnancy last year. She is sexually active now and is frequently forgetting her pills. Her partner will not use condoms. What are her contraceptive options?

51 #5 34 year old G0P0 graduate student with history of CIN3 treated with LEEP 2 years ago. She smokes 3/4 ppd of cigarettes and has a blood pressure on 3 separate readings of 145/92. She developed migraines without aura while using a COC 10 years ago. She is taking Dilantin for a recently diagnosed seizure disorder and was told by her home healthcare provider to get on birth control because she shouldn t get pregnant while taking this medication. What are her contraceptive options?

52 # 6 A 28 year old graduate student is tired of taking pills, and has side effects to everything She asks you what is the most effective, easiest method there is?

54 References J. Dinger, L. Heinemann, D. Kühl-Habich The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance study on Oral Contraceptives based on 142,475 women-years of observation. Contraception, Volume 75, Issue 5, Pages L. Heinemann, J. Dinger Range of published estimates of venous thromboembolism incidence in young women. Contraception, Volume 75, Issue 5, Pages Van den Heuvel MW, van Bragt AJ, Alnabawy AK, Kaptein MC. Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive. Contraception. 2005;72: Jick SS, Kaye JA, Russmann S, Jick H. Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol. Contraception. 2006;73: Cole JA, Norman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol. 2007;109: S. Jick, J. Kaye, L. Li, H. Jick Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 µg of ethinyl estradiol. Contraception, Volume 76, Issue 1, Pages 4-7 Boston Collaborative Drug Surveillance Program. Post Marketing study of OrthoEvra and levonorgerstrol oral contraceptives with 30 mcg EE in relation ro non-fatal VTE, ischemic stroke and MI trials.gov/ct2 Scholes, D, LaCroix, AZ, Ichikawa, LE, et al. Injectable hormone contraception and bone density: results from a prospective study. Epidemiology 2002; 13:581. Copyright 2002 Lippincott Williams and Wilkins. A. Kaunitz, P. Miller, V. Rice, D. Ross, M. McClung Bone mineral density in women aged years receiving depot medroxyprogesterone acetate: recovery following discontinuation. Contraception, Volume 74, Issue 2, Pages Dogterom P, van den Heuvel MW, Thomsen T. Absence of pharmacokinetic interactions of the combined contraceptive vaginal ring NuvaRing with oral amoxicillin or doxycycline in two randomised trials. Clin Pharmacokinet. 2005;44: Barry D. Dickinson PhDa,,, Roy D. Altman MDa, Nancy H. Nielsen MD, PhDa, Melvyn L. Sterling MD and The Council on Scientific Affairs, American Medical Association. Drug interactions between oral contraceptives and antibiotics Holt VL; Cushing-Haugen KL; Daling JR Obstet Gynecol 2002 May;99(5 Pt 1): Body weight and risk of oral contraceptive failure. Holt VL; Scholes D; Wicklund KG; Cushing-Haugen KL; Daling JR Obstet Gynecol 2005 Jan;105(1): Body mass index, weight, and oral contraceptive failure risk. L. Brunner, C. Hogue The Role of Body Weight in Oral Contraceptive Failure: Results from the 1995 National Survey of Family Growth. Annals of Epidemiology, Volume 15, Issue 7, Pages

Risk of venous thromboembolism in users of non-oral contraceptives Statement from the Faculty of Sexual and Reproductive Healthcare

Risk of venous thromboembolism in users of non-oral contraceptives Statement from the Faculty of Sexual and Reproductive Healthcare New data A paper published in May 2012 in the British Medical Journal