Clinical Challenges in Contraception and HIV

Educational Objectives

The goals of this program are to improve management of the contraceptive needs of women with medical conditions and the gynecologic and obstetric care of women with HIV. After hearing and assimilating this program, the clinician will be better able to:

1.   Discuss the efficacy, benefits, and drawbacks of different methods of contraception.

2.   Recognize contraindications for the use of combination oral contraceptives.

3.   Prescribe appropriate contraceptive methods for women with medical conditions.

4.   Determine the appropriate cervical cancer screening interval for women with HIV infection.

5.   Implement preconception and obstetric care in HIV-positive women.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Mishell is on the Advisory Committee for Bayer, Schering Plough, Warner Chilcott, Barr Laboratories, and Ortho-McNeil. Dr. Co­han received an investigator-initiated research grant from Pfizer. In her lecture, Dr. Cohan discussed the off-label or investi­gational use of a therapy, product, or device. The planning committee reported nothing to disclose.

Acknowledgments

Dr. Mishell was recorded at 13th Annual Post-Graduate Course on Pediatric, Adolescent and Young Adult Gynecology, spon­sored by Mount Sinai School of Medicine, and held April 3, 2009, in New York, NY. Dr. Cohan was recorded at OB/GYN Up­date: What Does the Evidence Tell Us, sponsored by the University of California, San Francisco, School of Medicine, and held October 22-24, 2008, in San Francisco. The Audio-Digest Foundation thanks the speakers and the sponsors for their coopera­tion in the production of this program.

Contraception for Women with Medical Diseases

Daniel R. Mishell Jr, MD, Professor, Department of Obstetrics and Gynecology, Keck School of Medicine, Uni­versity of Southern California, Los Angeles

General considerations: pregnancy-related mortality ratio in United States 11.5; 50% of deaths due to medical prob­lems; 50% of pregnancies unintended; pregnancy termination in United States highest of any developed country; 50% of women with unintended pregnancy used contraception in month of conception; teenagers (women 15 to 19 yr of age) —pregnancy rate decreased in 2002 compared to 1994, but percentage of unintended pregnancies in­creased; slight decrease in number of pregnancy terminations; percentage using no contraception decreased be­tween 1994 and 2001; use of condoms, oral contraceptives (OCs), depot-medroxyprogesterone acetate (DMPA; eg, Depo-Provera) and withdrawal increased; no contraceptive use, use of less effective methods, and inconsistent use of effective methods reasons for high incidence of unintended pregnancy

Contraceptive methods: highly effective  —  pregnancy rates <1% per year; sterilization; copper intrauterine devices (IUDs); levonorgestrel-releasing intrauterine systems (LNG-IUS; eg, Mirena); DMPA (intramuscular and subcu­taneous); single subdural implant; effective  —  combination OCs (COCs); transdermal patch; vaginal ring; pro­gestin-only OCs; less effective  —  barrier methods; natural family planning; withdrawal

ParaGard IUD: <2% cumulative pregnancy rate at end of 10 yr; can be used in teenagers

LNG-IUS: 5-yr method; £1% cumulative pregnancy rate; nulliparity and nulligravity not contraindications for IUDs; do not cause infection in women without Chlamydia or gonorrhea at time of insertion; no increased risk for infertility after use; long-acting method; requires only one visit to health care professional for 5 to 10 yr of easily reversible contraception; 400 µg misoprostol sublingually 8 hr before inserting IUD facilitates insertion and does not increase rates of expulsion

DMPA: reversible after delay of 6 to 9 mo; causes abnormal uterine bleeding; 50% of patients amenorrheic at 1 yr; associated with decrease in bone mineral density (BMD); however, no evidence of increased fracture rate; measurement of BMD or use of bisphosphonates not recommended in teenagers using DMPA

Single subdermal implant: single progestin-only rod; lasts 3 yr; causes irregular bleeding; estrogen can be added to eliminate bleeding;  less synthesis of androgenic progestin with newer formulations, thus fewer associated side effects; still associated with risk for venous thromboembolism (VTE)

OCs: no progestin-like substances; current formulations decrease hormone-free interval; one formulation approved for daily continuous use

Transdermal patch: worn 1 wk and replaced weekly for 3 wk; fourth week patch-free to allow for withdrawal bleed­ing; higher doses of estrogen cause concern about increased risk for VTE (conflicting studies); safe and effective

Vaginal ring: worn 3 wk and removed 1 wk to allow for withdrawal bleeding; 15 µg of ethinyl estradiol per day; ex­cellent bleeding pattern; self-insertion and removal

Categories of contraceptives: estrogen plus progestin  —thrombophilic; COCs, transdermal patch, and vaginal ring; progestin only  —  not thrombophilic; progestin-only OCs; DMPA injections; steroid-releasing IUDs (LNG) and implants; no steroids  —  copper IUD

Metabolic effects of steroids: estrogen increases hepatic globulin synthesis (including clotting factors and angioten­sinogen); progestin decreases sex hormone binding globulin (SHBG; no effect on globulin synthesis)

Thrombophilic effects of contraceptives: do not appear to be dose-related between 20 and 35 µg of estrogen; estra­diol used postmenopausally metabolized rapidly (not thrombophilic); ethynyl estradiol in contraceptive patch me­tabolized slowly (can cause thrombophilia); studies show no significant increase in VTE with progestin-only OCs and DMPA; risk for VTE with COCs  —  baseline incidence 4 per 10,000 woman-years (previously believed to be 1.0); approximately doubled with COCs and 5-fold higher with pregnancy; risk factors for VTE with COCs  —  obesity; older age; surgery; presence of hereditary thrombophilia; postpartum period; long distance travel; smoking and varicose veins do not increase risk for VTE; factor V Leiden and COCs  —  increased risk for VTE (synergistic, not additive); incidence 30 per 10,000 woman-years; women with positive screen have small absolute risk of devel­oping VTE; routine screening not cost-effective; consider progestin-only contraceptive in women with family his­tory of VTE or IUD without screening

Obesity: most recent studies show no decrease in effectiveness of COCs with high body mass index (BMI); risk for VTE  —  in women not taking COCs, risk with BMI >30 double that of women with BMI <25; with COC use, risk increases 2- to 5-fold for obese women, relative to women with BMI <25; use of COCs in obese women category 2 risk (benefits outweigh risks); risk factors for arterial thrombosis with COC use  —  smoking and age >35 yr; uncon­trolled hypertension; diabetes with vascular disease; atherosclerosis; other arterial disease; no increased risk in nor­motensive women >35 yr of age who smoke

World Health Organization (WHO) medical eligibility criteria for contraceptive use: category 1  —  no restric­tion; category 2  —  benefits outweigh risks; category 3  —  risks outweigh benefits; category 4  —  unacceptable health risk

Medical conditions: history of VTE or pulmonary embolism (PE)  —  COCs category 4; progestin category 2; copper IUD category 1; family history of VTE  —  COCs category 2; obesity  —  COCs category 2; ischemic heart disease  —  COCs category 4; progestin category 3; copper IUD recommended; hypertension  —  COCs category 4 if uncontrolled and category 3 if controlled; progestin category 2; copper IUD category 1; smoking  —  if <35 yr of age, COCs category 2; switch to progestin product at older age; hyperlipidemia  —  estrogen plus progestin cate­gory 2; use progestin-only product or IUD in women with hypertriglyceridemia; headache  —  migraine headache with aura increases risk for cerebrovascular accident (CVA) in women using COCs; no contraindication for any hormonal contraceptive with nonmigraine headache; COCs can be used in woman <35 yr of age with migraine without aura; >35 yr of age category 3; valvular heart disease  —  COCs can be used in patient with asymptomatic mitral valve prolapse unless patient has classic migraine or history of other cerebral event, atrial fibrillation or congestive heart failure, history of thrombotic effect, or mechanical valves; diabetes  —  COCs category 1 with history of gestational diabetes; can use estrogen-containing contraceptive, progestin, or IUD if noninsulin-depen­dent or insulin-dependent without vascular disease; estrogen contraindicated in women with vascular disease or diabetes >20 yr; no evidence COCs worsen type 1 or 2 diabetes or increase likelihood of insulin-dependence in women with gestational diabetes; epilepsy  —  progestin decreases seizure frequency and estrogen lowers seizure threshold; speaker recommends DMPA or progestin-only agent; anticonvulsant drugs interfere with estrogen me­tabolism; more unscheduled bleeding and possibly less efficacy; second generation anticonvulsants do not inter­act with contraceptive steroids; depressive disorders and thyroid disease  —  no contraindications with any method; breast disease  —  estrogen-containing agent contraindicated with personal history of breast cancer; data show no increased risk for breast cancer, including women with BRCA gene mutation, and reduced risk for endo­metrial and ovarian cancer associated with OCs; can be used if woman has first-degree relative with history of breast cancer; anemias  — increased blood loss with copper IUD; no increased blood loss with hormonal agents; systemic lupus erythematosus  — estrogen appropriate, unless vascular disease present; HIV/AIDS  —IUD appro­priate in immunocompromised women; can be used with antiretrovirals (ARVs); efficacy of COCs not compro­mised by concomitant antibiotic use, except rifampin; may be compromised by concomitant prolonged use of oral antifungal; contraindications for COCs  —cholestatic jaundice of pregnancy or jaundice with previous OC use; current or past history of thrombophlebitis; cerebrovascular or coronary artery disease; cancer of breast, en­dometrium, or other estrogen-dependent neoplasia; undiagnosed abnormal genital bleeding; hepatic adenomas or carcinomas

Healthy women with special conditions: COCs appropriate for women with polycystic ovarian syndrome, women with first-degree relative with breast cancer, or women using nonsteroidal anti-iflammatory drugs; contraindi­cated in women with first degree relative with history of VTE or asymptomatic women with factor V Leiden mu­tation (even without thrombosis); speaker does not recommend estrogen-containing products for women with BMI >40 (including postmenopausally); consider long-acting reversible methods for teenagers (eg, IUD, im­plant)

Obstetric and Gynecologic Care for the
HIV-Infected Woman

Deborah Cohan, MD, MPH, Associate Professor, Department of Obstetrics and Gynecology, University of California, San Francisco, School of Medicine

Epidemiology (2006): »25% of HIV-positive adults in United States women; HIV/AIDS number one cause of death for black women 25 to 34 yr of age; fifth most common cause of death among all women in higher age brackets; 40% of HIV-infected infants born to women unaware of HIV status until after delivery; testing recommendations  —  testing of all women 13 to 64 yr of age, regardless of risk factors, at least once; annual testing of women with high-risk sexual or drug-using behavior; universal, opt out (routine, but voluntary) prenatal HIV testing; repeat third-tri­mester testing in certain states; rapid HIV testing in labor and delivery unit

Cervical cancer screening and treatment: human papillomavirus (HPV) vaccine not likely beneficial because of high baseline prevalence of preexisting HPV infection; Papanicolaou (Pap) testing  —sensitivity 63% to 81%, spec­ificity 84% to 97%; data show women more likely to adhere to Pap testing when gynecologic and HIV care inte­grated; screening interval  —  every 6 mo initially, annually if first 2 tests normal; squamous intraepithelial lesion (SIL)  —  more likely in HIV-positive women with low CD4 count than in HIV-negative women; no evidence of pro­gression from normal to high SIL in <1 yr; atypical cells of undetermined significance (ASC-US)  —  more likely with HIV infection; small risk for invasive cancer; risk for HIV-positive woman approximately twice that of HIV-negative woman; 17% risk for cervical intraepithelial neoplasia (CIN) I, and »15% risk for CIN II to III with ASC-US and HIV-positivity; CD4 count not associated with increased risk for underlying dysplasia in setting of ASC-US; colposcopy recommended for HIV-positive woman with ASC-US or worse; treatment  —  indications same, re­gardless of HIV status; excision or ablation options; cryotherapy not well evaluated; treatment associated with re­gression in women with high-grade SIL; no difference in progression or regression with treatment in low-grade SIL ; highly active antiretroviral treatment (HAART) associated with decreased risk for recurrence; no evidence CD4 count should alter posttreatment follow-up

Contraception: combination hormonal methods  —  significant drug-to-drug interaction with some AVRs; dual con­traception important for woman in discordant partnership; possible genital tract shedding with progestin-only OCs; data suggest DMPA associated with increased viral setpoint; altered pharmacokinetics with hormonal contracep­tives and ARVs  —  unknown whether interaction leads to unintended pregnancy; <35 µg OC not recommended for woman on ARV therapy; transdermal patch or vaginal ring appropriate options; IUDs  —  no evidence of increased infectious complications or increased genital tract shedding among HIV-infected women, compared to HIV-nega­tive women; no evidence of decreased efficacy with severe immunosuppression; ongoing studies looking at whether LNG-IUS associated with HIV genital tract shedding; WHO eligibility criteria category 2

Preconception issues: HIV not believed to have negative impact on pregnancy; some evidence of slowing of HIV progression in pregnancy; <1% risk for vertical transmission if woman has undetectable viral load (VL) at delivery; optimize ARV therapy with goal of total viral suppression; ensure patient using only safe medications; avoid efavi­renz, especially preconceptionally and in first trimester; initiate prophylaxis for opportunistic infection; increase fo­late supplementation if woman on folate antagonist; confirm vaccinations current (only inactivated vaccines); contraception while optimizing health; optimize pregravid weight; psychosocial referrals; smoking, alcohol, and recreational drug cessation; efavirenz (EFV)  —  animal and human data show association with neural tube defects (NTDs); be aware of coformulations

Goals of prenatal care: optimize maternal health; prevent vertical transmission of HIV; minimize maternal and fetal risk; prepare for or prevent subsequent pregnancies; starting ARV therapy  —  risk for transmission highest in intra­partum period (majority in late third trimester); AVR typically started at ³12 wk gestation, unless continuing pre­conception regimen or if woman needs ARV immediately for own health; some protease inhibitors require increased dose in third trimester to maintain adequate levels; what to avoid  —  nevirapine associated with signifi­cant maternal hepatotoxicity, particularly with baseline CD4 count >250 cells/mm³; stavudine with or without di­danosine associated with significant lactic acidosis and maternal morbidity; nelfinavir teratogenic, carcinogenic, and mutagenic in animals (no human data)

Obstetric risk factors: VL strongest predictor for vertical transmission; chorioamnionitis (minimize number of ex­aminations); sexually transmitted infection in labor (probably related to genital tract shedding of HIV); invasive fe­tal procedures; does not appear to be association between duration of rupture of membranes and transmission in women on HAART; intrapartum management  —  ARV, including intravenous zidovudine (provides preexposure prophylaxis for baby); avoid artificial rupture of membranes unless delivery imminent; protease inhibitors or efavi­renz can increase methylergonovine (Methergine) level; elective cesarean delivery not shown beneficial in reducing risk for vertical transmission; trial of labor appropriate if VL <1000 copies/mL

Postpartum management: continue ARVs if CD4 nadir <350 cells/mm³; bottle feeding recommended; contracep­tion; measles, mumps, rubella (MMR) vaccination probably safe in HIV-positive patient with CD4 count >200 cells/mm³ for ³3 to 6 mo; speaker recommends tetanus, diphtheria, and pertussis vaccine during pregnancy

Editor’s Notes

National Perinatal HIV Consultation and Referral Service: 1-888-4765

Human Milk Bank Association of North America: www.hmbana.org/index.php?mode=locations

US Preventive Services Task Force Guidelines: http://aidsinfo.nih.gov

Antiretroviral Pregnancy Registry: www.APRegistry.com

Suggested Reading

Aaron E et al: Gynecologic care and family planning for HIV-infected women. AIDS Read 15:420, 2005; ACOG Committee on Obstetric Practice: ACOG committee opinion number 304, November 2004. Prenatal and perinatal human immunodefi­ciency virus testing: expanded recommendations. Obstet Gynecol 104:1119, 2004; Berg CJ et al: Pregnancy-related mortality in the United States, 1991-1997. Obstet Gynecol 101:289, 2003; Cohan D et al: HIV testing attitudes and practices among cli­nicians in the era of updated Centers for Disease Control and Prevention recommendations. J Acquir Immune Defic Syndr 50:114, 2009; Danso D et al: Cervical screening and management of cervical intraepithelial neoplasia in HIV-positive women. Int J STD AIDS 17:579, 2006; Heard I: Prevention of cervical cancer in women with HIV. Curr Opin HIV AIDS 4:68, 2009; Heinemann LA et al: Range of published estimates of venous thromboembolism incidence in young women. Contraception 75:328, 2007; Marchbanks PA et al: Oral contraceptives and the risk of breast cancer. N Engl J Med 346:2025, 2002; Rah­angdale L et al: Rapid human immunodeficiency virus testing on labor and delivery. Obstet Gynecol 112:159, 2008; Rosen­berg MJ et al: Performance of the TCu380A and Cu-Fix IUDs in an international randomized trail. Contraception 53:197, 1996; Sidney S et al: Venous thromboembolic disease in users of low-estrogen combined estrogen-progestin oral contracep­tives. Contraception 70:3, 2004.