Contraceptive Technology Faculty Update Leigh Beasley, MD, FAAFP Emory University Regional Training Center Satellite Conference and Live Webcast Atlanta, Georgia Wednesday, October 25, 2006 2:00 - 4:00 p.m. (Central Time)

Produced by the Alabama Department of Public Health Video Communications and Distance Learning Division

Program Objectives Program Objectives • Describe current thinking on • Describe the new World Health Organization's (WHO) medical contraceptive efficacy and the status eligibility criteria; Intrauterine Device of experimental contraceptives. (IUD) and teens, IUD and Plevic Inflammatory Disease (PID); • Describe the interrelationships of spermicides; and known medical contraception methods with thrombogenic mutations and oral specific drugs, reproductive contraceptives. disorders and other health problems. • Discuss management of common contraceptive problems.

Contraceptive Use in the Half of All Pregnancies in the US: 2002 Report United States Each Year Are • Percentage of men and women who Unintended used contraception ranged from 67% Unintended Pregnancy- (Guam) to 88% (Idaho). Miscarriage 6% Unintended • Women reported OC’s as the Pregnancy- Intended Birth Pregnancy- predominant method in 49 areas 19% Birth 43% followed by tubals, condoms and vasectomy. • Men reported tubal, vasectomy, OC’s, Unintended and condoms. Pregnancy- Abortion Intended 23% Pregnancy- • Note lack of “new methods” in the top Miscarriage Pregnancies four. 9% (6.3 Million)

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The Oral Contraceptive Cycle OC Developments • Progestin prevents luteinizing • New Progestin: Drospirenone; hormone (LH) surge. • Estrogen suppresses follicle- Yasmin. stimulating hormone (FSH) and follicular development. • Berlex has obtained FDA approval • Together, the hormones in for Yaz (20 mcg EE/3 mg combination OCs inhibit proliferative changes in drospirenone) for BC and PMDD uterus, leading to endometrial (unique dosing 24 days active pills atrophy. and 4 placebo pills). • When placebo pills are taken, a “pill period” results.

OC Developments Depo-Provera • New Estrogen doses: 25mcg; • November 17, 2004: the FDA issued a Cyclessa, Ortho-Tricyclen Lo. “black box” warning recommending • Extended Cycle Use: Seasonale, that Depo-Provera be used long-term Seasonique. (i.e. more than two years) only if all • Widening EC use. other pharmacologic contraceptives • “Natural” estrogen pills and are not appropriate or tolerated due nonsteroidal progesterone agonist (tanaproget). to bone loss data in adult women.

Depo-Provera and Effect of Contraception on BMD in Teens Bone Mineral Density • NIH-funded study (J. Adoles Health 2004) • Studied women ages 18-33 seeking – 370 girls (mean age, 15). contraception. – 53 chose Depo, 165 chose OC’s (20 ug of estrogen) and 152 chose no • Injectable Depo hormonal contraception. medroxypgogesterone acetate – BMD values after 12 months. 150mg vs. 0.030 mg EE plus 0.15 mg • At lumber spine: -1.4%, +2.3% and desogestrel vs. 0.035 mg EE plus 1.0 +3.8%. mg norethindrone vs. controls (no • At the hip: -2.2%, +0.3% and +2.3%. hormonal contraception). – Clinical relevance ? • Followed for 2 years.

2 Effects of Contraception on DMPA and Bone Health Bone Mineral Density • Three studies that indicate BMD is • Depo users-average loss from baseline comparable in former and never of 5.7 % (in spinal BMD). users following discontinuation of • Desogestrel OC-average loss form DMPA. baseline of 2.0 % (not statistically – Petitti DB et al (Obstet Gynecol significant). 2000;95:736-744). • Norethindrone- no significant change – Scholes D et al (Epidemiology in BMD. 2002; 13:581-587). • Controls-average gain of 2.6 % in BMD. – Scholes D et al (Arch Pediatr • Clinical relevance? Adolesc Med 2005; 159: 139-144).

Effect of Pregnancy DMPA and Bone Health and Lactation on Bone • Data presented at the May 2005 Mineral Density ACOG meeting (co-author Andrew • Bone turnover is reduced in early Kaunitz, MD). pregnancy, returned to normal during the third trimester and increased in • Loss of BMD of approximately 1%- postpartum lactating women 2% annually, with slower loss after (Cole et al. 1987) that and substantial recovery • No evidence that high parity is following discontinuation (followed associated with an increased incidence patients for 2 years after DMPA was of osteoporotic fractures in later life discontinued). (Alffram, 1964; Walker et al. 1972).

DMPA and Bone Health World Health Organization DMPA Statement • Complete recovery of BMD was not • July 2005: There should be no found at all skeletal sites assessed restriction on the use of DMPA, including no restriction on duration (but would it have if followed for > 2 of use, among women ages 18-45 years post DMPA?). who are otherwise eligible to use the method.

3 World Health Organization World Health Organization DMPA Statement DMPA Statement • Among adolescents (menarche to • Since the data are insufficient to less than 18) and women over 45, the determine if this is the case with long advantages of using DMPA generally term use among this age group, the outweigh the theoretical safety overall risks and benefits for continuing use of the method should concerns regarding fracture risk. be reconsidered over time with the individual user.

Lower Dose, Subcutaneous Lower Dose, Subcutaneous Depo-Provera Depo-Provera • Study compared LDSQ Depo • Ovulation was suppressed in all (104mg/0.65ml) with IM Depo participants for at least 3 months. (150 mg/ml). • Median time to return to ovulation • Confirmed study participants were was similar in the two groups (183 ovulatory. days in the IM group and 212 days in • Received single injection and the SQ group). followed up until they ovulated • Dose and maximum serum (up to 12 months). concentration are substantially lower • 19 women who received IM and 39 with the SQ formulation…so ? Less received SQ were evaluated. side effects?

NuvaRing NuvaRing®: Metabolic and • Non-biodegradable, flexible, Safety Conclusions transparent vaginal ring. • Minimal effect on lipid parameters. • Contains two active components: • No clinically relevant effect on ethinyl estradiol and etonogestrel (an estrogen and a progestin). carbohydrate metabolism. • Releases 0.015 mg/day of • Minimal effect on hemostatic ethinylestradiol and 0.120 mg/ day of variables, comparable with 30 EE/150 etonogestrel over a three week period. LNG COC.

4 NuvaRing®: Metabolic and Nuva Ring Update Safety Conclusions • Effectiveness not lower in very heavy • Low androgenic effects. women (Westhoff-ACOG 2005).

• No adverse effect on blood pressure. • Continuous use can be based on a “calendar approach” since the Nuva • No unfavorable effects on the cervix Ring is active for 35 days, not 21 and vagina. (Timmer et al Clin Pharmokin 2000;39:233). • Clinicians can obtain free fitting rings by going to www.nuvaring.com

California Women’s Health Emergency Contraception: Survey • 6198 women (age 18-44) were asked The Nations Best-Kept “If a woman has unprotected sex, is there anything she can do in the 3 Secret days after intercourse that will prevent pregnancy?” – Slightly more than _ said yes, 1/3rd said no and around 10% said they didn’t know.

California Women’s Health Why Everyone Should Know Survey About EC 43% of the decrease in abortions in – 19% of those who answered yes • the US in the last 5 years has been listed incorrect responses to “what attributed to the use of EC. can she do?” (included RU 486 and • Up to 51,000 pregnancies are prevented annually by the use of EC. douche) and 7% gave ambiguous • (Finer et al. Perspec on Sexual answers (“seek medical help”). and Reprod health 2003) • Works like LAM.

5 Emergency Contraception EC’s Effects on Ovulation • Studied 58 women with regular Mechanism of Action menstrual cycles (either had tubals • Inhibition of ovulation. or IUD). • Decreases the probability of • Treatment regimens: two 0.75 mg fertilization after ovulation. doses of levonorgestrel (12 hours • Changes in the endometrium apart), single 0.75 mg dose of (decreasing the likelihood of levonorgestrel plus placebo or double dose of placebo. implantation). • Randomized to take meds when • Does NOT interfere with an leading follicle reached a diameter of established, post implantation 12-14 mm (Group I), 15-17 mm pregnancy. (Group II) and > 18 mm (Group III).

EC’s Effects on Ovulation EC’s Effects on Ovulation • Within 5 days of treatment, there was • Percentage of cycle either ovualtory no ultrasound evidence of follicular dysfunction or no follicular rupture rupture (i.e., no ovulation) in 44%, was similar in with 3 regimens in 50% and 36% of cycles with 2 levo. Group 1, significantly higher with doses, 1 dose and placebo. levo than placebo in Group II and • Ovulatory dysfunction (disordered significantly higher with one dose surges in LH and FSH) in 35%, 36% levo than placebo in Group III. and 5%.

EC’s Effects on Ovulation Emergency Contraception • Caution in interpreting results: used • Most effective if taken within 72 hormonal parameters and ultrasound hours of unprotected intercourse and did not test EC’s efficacy. (the sooner the better). • 13% of women with dominant follicle • New data suggests equal (i.e. > 18 mm) did not ovulate when effectiveness if both doses are taken treated with placebo. together and may be used up to 120 • Single dose used in this study was hours after unprotected intercourse. not the “single dose” used in • EC treatment is indicated regardless treatment studies. of the cycle day on which – (Contraception 2004 Dec.) unprotected intercourse occurred.

6 Emergency Contraception Mirena – A Levonorgestrel • No absolute contraindications. Releasing System • T-shaped frame, 32 mm in length, • Initiate long term contraception that holds a cylinder that contains immediately following EC levonorgestrel. (emergency contraception does NOT continue to prevent pregnancy • Releases levonorgestrel into the during the rest of the cycle). uterine cavity at a rate of 20 mcg a • Resumption of next menstrual cycle. day. • Over the counter status. • Approved for five years of use.

Plasma Concentrations of Mirena – A Levonorgestrel- Levonorgestrel Releasing System

9000 • Safety: 8000 8000 – Ectopic pregnancy 7000 6000 • One of 5 contraceptive failures 5000 associated with the Mirena is an 4000 3000 ectopic pregnancy, resulting in 2000 an annual ectopic pregnancy 1000 0 rate of 0.02%. Plasma concentrations (pg/mL) Plasma concentrations (pg/mL) LNG IUS ImplantImplant Mini-pill Combined OCs

Mirena – A Levonorgestrel- LNG IUS as Alternative to Releasing System Hysterectomy • Changes in bleeding pattern: 70 – Initially there is an increase in Women bleeding days (menstrual days and 60 Canceling intermenstrual spotting days 50 Hysterectomy combined). 40 Percent – Irregular spotting during the first 3-6 Percent 30 months. 20 – Bleeding may remain irregular in some women. 10 – ~20% will become amenorrheic within 0 the first year of use. LNG IUS Medical Therapies

7 Paraguard Perhaps the Copper IUD is • Lasts 10 years. Permanent, Reversible Contraception? • Highly effective. • In 1984, the FDA approved the • Has no systemic effects (e.g. headaches, acne). copper IUD for 4 years of use. • Most women have regular menses. • Eventually the FDA said it was “good • Women may experience increased for up to 10 years.” duration of menses and increased amount of bleeding.

Perhaps the Copper IUD is Paraguard Package Insert Permanent, Reversible Contraception? • The new insert does not recommend that this IUD be avoided by women • WHO reported the copper IUD was effective for 12 years (contraception who are: 1997;56:341). – Nulliparous. • Brazilian study followed women up to 16 years of use..this study needs – Have a history of PID. corroboration. Explusion (? caused by fibroids?) may be a concern (contraception 2005 Nov; 72:337-41).

Ortho Evra “Seventeen Deaths in Users Contraceptive Patch of Ortho Evra Patches” • Once-a-week combination hormonal • In October 2004, AP found 17 deaths patch. among users of the Ortho Evra patch. • Changed on the same day of the week, • We know NOTHING about the three times a month, with the fourth denominator data and very little about week patch-free. the numerator number. • Carrier for ethinyl estradiol and • Two epidemiological studies may norelgestromin. reveal more about this rare but – EE – 20 µg released daily. serious complication. – Norelgestromin - 150 µg released daily. • Biologic plausibility.

8 FDA “Bolded” Message Distribution of Pregnancies by “You will be exposed to 60% more Baseline Body Weight Deciles estrogen if you use Ortho Evra than if (n=3319 subjects) Decile Weight you use a typical birth control pill Pregnancies (N) Range (kg) Total containing 35 mcg of estrogen. In 1 (334) <52 1 2 (285) 52 - <55 2 general, increased estrogen exposure 3 (354) 55 - <58 0 may increase the risk of side effects. 4 (256) 58 - <60 0 5 (433) 60 - <63 2 However, it is not known if there are 6 (346) 63 - <66 0 differences in the risk of serious side 7 (276) 66 - <69 1 effects based on the differences 8 (379) 69 - <74 0 9 (304) 74 - <80 2 between Ortho Evra and a birth control 10 (352) ≥80 7 pill containing 35 mcg of estrogen.” (80- <85) 1 (85- <90) 1 ≥90 (N=83) 5

Weight and Risk Weight and Risk of OC Failure of OC Failure • NICHD-sponsored study. • Risk ↑ in women with the highest • 618 OC users (2822 women-years OC body weight and taking low- (<50 use). mcg EE = 2.6x) and very low-dose (< – 106 confirmed pregnancies. 35 mcg EE = 4.5x) OCs. • Women in highest body weight quartile (>70.5 kg or 155 lbs) had 1.6 • Findings suggest that high body x significantly increased OC failure weight may compromise oral compared to women who weighed <155 lbs. contraceptive effectiveness.

Overweight Women Are at Contraceptive Patch Increased Risk for OC Failure Precautions • Study in Seattle: 248 women became • Body weight ≥198 lbs. (90 kg) pregnant while using OC’s and 533 – Results of clinical trials suggest age-matched controls did not. that the contraceptive patch may be less effective in women with • Odds of becoming pregnant while on body weight >198 lbs (90 kg) than OC’s were 58% higher for women in women with lower body weights. with BMI’s > 27.3 and were highest • No other changes. for women with BMI’s> 32.2. • Consider body weight in OC users –(Obstet Gynecol 2005 Jan.) also.

9 Single-Rod Implant Single-Rod Implant Contraceptive: Description Contraceptive Efficacy • Single 40-mm × 2-mm rod. • Rod is made of ethylene vinyl acetate • No pregnancies during 1200 woman- copolymer. years of exposure (Pearl Index, 0; • Contains 68 mg of etonogestrel (3- keto-desogestrel), the active 95% CI 0.0-0.2). metabolite of desogestrel, and comes in disposable sterile inserter. • Effective contraception that lasts for • Inhibits ovulation during the entire treatment period. 3 years. • Effective for 3 years.

FDA Approved July 2006 ESSURE • Implanon • New procedure for non-incisional – Return to fertility – 94% of women permanent birth control. ovulated within 3 weeks of removal. • Micro-inserts are placed in the – Side effects. fallopian tubes to prevent pregnancy. • Changes in vaginal bleeding (30% discontinuation). • The system is introduced with a • Amenorrhea. standard hysteroscopic approach • Weight changes (1.5% with tubal cannulation. discontinuation). • Can be performed without general • Acne (1.0% discontinuation). anesthesia.

Young Teenager with Severe Dysmennorrhea • 13 year old female, never sexually Contraceptive Case Studies active.

• Menses began at age 11 and painless for 6 months.

• Now periods are extremely painful, causing her to miss 1-2 days of school/month.

10 Young Teenager with Would You… Severe Dysmennorrhea A. Prescribe a stronger prescription • Tried heat, NSAIDS, aspirin, NSAID because OCP’s are not appropriate in this age group. exercise…nothing works. B. Start her on Depo Provera to • PE- normal B/P. decrease her menstrual bleeding. C. Do a pap smear and give her whatever method she wants. D. Defer the Pap and start her on OCP’s.

Contraception and What Factors Increase the Pap Smears Risk of Acquiring HPV? • Never sexually active women are at • Number of sexual partners. VERY low risk of HPV infection.

• Cervical cancer and HPV are linked. • Recent new partner (5-8 months).

• Comfort of young teens with their • Rate of new partners per month. bodies. • History of herpes. • New pap screening guidelines.

What Factors Decrease the What Factors Decrease the Risk of Acquiring HPV? Risk of Acquiring HPV? • Limited sexual exposure. • Various studies show different results for use of oral contraceptives. – But HPV can be acquired without – Winer: current oral contraceptives vaginal penetration. adjusted HR 1.41. – 8% of virgins tested positive in 24- – Xi:1.6 (short duration use) to 5.4 (5- month study. 8 mon use)2. – Moscicki: current oral – Condoms are not protective. contraceptives 0.543.

11 What Is the Risk for Will HPV Resolve? Developing Cervical Cancer? • Median time to resolution: • Approximately 10,000 cases in the United States per year. – Ho (1998) 8 months

• Cervical cancer risk is higher in – Woodman (2001) 13.7 months developing countries. – Richardson (2003) 13.2 months • Incidence of cervical cancer in – Xi (2002) HPV16 17.2 months adolescents is essentially zero.

What Screening Is “Oh my gosh, I didn’t have a Indicated? period, am I pregnant?!” • Current recommendations: • 18 year old G1P1 on OCP’s for 2 – Initiate Pap testing at age 21 or 3 years with no problems. years after initiation of sexual • C/O no period this month. activity, whichever comes first. • No symptoms of pregnancy. • Recommendations after vaccination: • Can I start my new pack of pills – Yet to be determined. Sunday?

Would you…. What About Family History? A. Tell her to call back on Monday and • 19 year old desires contraception, speak to an APRN and come in for a but doesn’t think she can remember pregnancy test. to take a pill every day. B. Tell her “sure, start your • Family history - father had MI at age pills”…”whatever”. 48, 29 year old sister has C. Inquire about missed pills during hypertension. the past month. • Patient is a college student, non- D. Tell her to stop her pills and start smoker, gets lots of exercise, normal thinking of baby names. blood pressure.

12 Would You Tell Her Post Partum Contraception A. You are healthy, you can start whatever method you like. • 21 year old, 6 weeks post partum, B. The NuvaRing has the lowest dose “fully breastfeeding”. of estrogen, you should consider it with your family history. • Married. C. With that family history, your only choice is non-hormonal • Afraid of IUD’s. contraception: a P-IUD or condoms. D. The patch might be the best choice • Normal B/P and pelvic exam. for you, if you can’t remember to take pills.

Post Partum Contraception Nausea and Contraception A. Any method is OK to use while • 22 year old G1P1 (child is 9 months breastfeeding. old). B. No need to worry about contraception for at least 6 months • No longer breastfeeding. while you’re breastfeeding. • Wants another baby when this one is C. Progestin-only methods (pills, M- 3 years old. IUD or Depo) are the best for you while breastfeeding. • Had hyperemesis gravidarum. D. You could use condoms and EC • Normal exam and B/P. while breastfeeding.

Well…. Acne and Weight Loss A. The Nuva Ring, M-IUD and Implanon • 18 year old G0P0 wants “that new pill all have low doses of hormones and may work for you. that’s good for acne and causes you B. You should stick with progestin only to lose weight”. pills since they’re working for you. C. You don’t really want another baby in • History of heavy periods. 3 years…Do you??!! D. The pills definitely won’t make you • Plays softball and takes Motrin “a nauseated after all that nausea of lot” for pain. pregnancy.

13 Yasmin Yasmin • Restricted labeling for drospirenone. • 30ug EE/3 mg drospirenone – Contraindicated in women with renal • Drospirenone insufficiency, hepatic insufficiency – Spironolactone analog with and adrenal insufficiency (patients at antimineralocortocoid and risk for hyperkalemia). antiandrogenic activity..which – Warning for patients on chronic means it’s also a diurectic. meds. – Limited data in use in women >30. • NSAID’s (long term use). – Good for acne and hirsutism…may • Potassium supplements. benefit patients who experience K+ sparing diurectics, ACE’s, “fluid retention and bloating” • ARB’s, heparin (check K+ level in during their cycles. 1st month for pts on these meds).

Drospirenone and Hypertension and Weight Loss Contraception • Same side effect profile. • 40 year old G3P3 on OCP’s for 5 • Same effectiveness. years. • 1 open label trial. – Small amount of temporary weight • Annual exam..B/P is 150/98. loss in first 6 months, at 1 year, weight returned to baseline or • B/P last year 120/80. slightly above. • (Contraception 2000, Eur. J Contra Reprod Health Care 2000)

Low Dose OCP’s and CV Risk Contraception and Number of Excess Cases of MI and “Migraine” Headaches Stroke Attributable to OC • 19 year old nulliparous patient. 20-24 30-31 40-44 years years years • c/o “migraine headaches”. Non-Smokers 0.4 0.6 2 Smokers 1 2 20 • B/P normal. Hypertension 4 7 29 • Exam and FH unremarkable. Number of Pregnancy Related Deaths (per 10 12 45 100,000 live births)

14 OCP’s and Migraine Smoking and Contraception Headaches • Increased risk of stroke in women > 45 • 34 year old G2P2 on OCP’s for 8 years with migraines. years. • Migraine with aura is associated with • Smokes _-1 pack of cigarettes/day. greater risk than migraine without aura. • Likes that her periods are regular on • WHO states prescribing OCP’s to the pill. women < 35 years with migraine without aura is safe. • Doesn’t want a tubal. • “Menstrual migraines” may improve on OCP’s. • Turns 35 years old next month.

Age and Contraception Contraception and CAM • 38 year old G2P2 with history of • 42 year old G3P3 on OCP’s for 12 hypothyroidism and irregular menses years. and “perimenopausal” symptoms. • Non-smoker. • On Progesterone cream and “natural thyroid replacement”. • B/P normal (120/70). • Worried that “condoms aren’t enough”. • Doesn’t want an IUD or tubal. • Doesn’t want “more hormones” now • Partner doesn’t like condoms. that she’s “getting better with natural meds”.

Complicated Patient OCP’s and Inherited • 30 year old G3P3 (living children 1). Hypercoagulable States • In OCP user: • Had 2nd trimester fetal demise, 3rd – Risk of VTE increases 35-99 fold in child born with congenital cardiac carriers of Factor V Leiden. defect. – Risk of VTE in carriers of Protein C • History of DVT between 2nd and 3rd and antithrombin deficiency increased pregnancy. 2 fold and 9 fold respectively. – Safety of progestin only • Diagnosed with Anticardiolupin contraceptives in hypercoagulable Antibody, Factor 5 Leiden. states in unknown.

15 Complicated Patient Non-Contraceptive Benefits

• 41 year old G7P0. • 39 year old G2P2.

• Non-smoker. • S/P BTL after last child (age 6).

• Regular menses. • Non-smoker. • Married/monogamous relationship. • Heavy, irregular menses. • History of OCD.

What Now? Any Suggestions? • 24 year old G3P2. • 18 year old G3P2 (currently 24 weeks pregnant). • Non-smoker. • 2 prior C-sections, Wants a tubal this • Conceived first child while on OCP’s, time. conceived second child while using • Can’t remember to take pills, weighs the patch, got pregnant with third 240 pounds, doesn’t want an IUD, child with P-IUD in place. tried the ring and didn’t like it, doesn’t like Depo, partner won’t use • Doesn’t want sterilization. condoms.

Upcoming Programs Ensuring Quality in the Collaborative Practice Agreement Thursday, October 26, 2006 10:00 a.m. - 12:00 Noon (Central Time)

Infection Control Update Wednesday, November 1, 2006 2:00 - 4:00 p.m. (Central Time)

For complete list of upcoming programs visit: www.adph.org/alphtn

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