Special Considerations for Women of Reproductive Age on ...



Special Considerations for Women of Reproductive Age on Anticoagulation

January 2012

Pharmacy Benefits Management Services, Medical Advisory Panel, VISN Pharmacist Executives and Women’s Health Strategic Healthcare Group

Below are points for health care providers (e.g., anticoagulation management providers, primary care providers, nursing, clinical support staff, etc.) to consider when managing and counseling women of reproductive age who are receiving anticoagulation therapy.

Unique issues for women of reproductive age:

▪ Menstrual problems can be exacerbated by anticoagulation.[i]

▪ Warfarin is a known teratogen.[ii] Data on the safety of use of newer anticoagulants including dabigatran or rivaroxaban during pregnancy is not yet available.

▪ Hemorrhagic ovarian cysts, which can be life-threatening, are estimated to affect 1% of women receiving anticoagulation medications.[iii]

▪ Pregnancy and the postpartum period increase women’s risk of thrombosis and therefore require careful planning and awareness of the potential signs/symptoms of thrombotic events.

▪ Warfarin is considered safe to use while breastfeeding.[iv]

Recommended strategies for identification and evaluation of issues specific to women of reproductive age:

▪ Assess menstrual difficulties

o Menstrual problems may be subjective (i.e., perceived as being a problem by the patient) and/or objective.

o Symptoms of anemia include fatigue, and/or shortness of breath with exercise.

o Suggestions for questioning patients:

▪ Have menses been more of a problem since starting anticoagulation?

▪ Is she troubled by cramping or excess bleeding with menses?

▪ Assess anticoagulant medication adherence

o Without guidance regarding alternative strategies to control heavy menses, women may self-decrease their warfarin dose to reduce menstrual flow. This can be life threatening.

▪ Assess potential for unintended pregnancy

o Warfarin is a known teratogen and can cause birth defects when used by pregnant women.

o Pregnancy testing is recommended prior to initiation of warfarin.

o Routinely assess and confirm the use of effective contraception (see Prevention of Medication induced Birth Defects).

Recommended management of issues specific to women of reproductive age:

Note: There are benefits and risks of using and not using hormonal treatments in women at increased risk of thromboembolism that should be considered on an individual basis. The US Centers for Disease Control (CDC) Medical Eligibility Criteria for Contraceptive Use may be consulted for additional information regarding use of hormonal and non-hormonal treatments in women with certain characteristics or medical conditions.[v]

▪ Controlling Heavy Menses

o All progestin-containing contraceptives reduce menstrual flow.

▪ Progestin-only preparations may be preferable over estrogen-containing preparations for use in patients at increased thromboembolic risk (such as those requiring anticoagulation), as current evidence suggests they do not increase thromboembolic risk.4,[vi],[vii]

▪ Progestin-only products include: progestin-only pills (norethindrone 0.35 mg, sometimes called “mini-pills” or “POPs”), depot medroxyprogesterone acetate (DMPA) injection, levonorgestrel-containing intrauterine device (IUD) (Mirena), etonogestrel implant (Implanon).

▪ The only contraindication to use of progestin-only contraceptives is a history of breast cancer.4

▪ The levonorgesterel-bearing IUD is more effective than DMPA in controlling menses.[viii],[ix],[x]

▪ The levonorgesterel IUD can be safely placed for and used by women who are anticoagulated.[xi],[xii]

o Women should be advised to avoid non-steroidal anti-inflammatory drugs (NSAIDs) which they may have previously used to control menstrual cramping while on anticoagulation.

o The efficacy and safety of the use of tranexamic acid in patients at higher risk for thromboembolism (such as those requiring anticoagulation) have not been established, but in general, these patients should not receive tranexamic acid.

o Suggestions for counseling:

▪ Patients should be counseled on the importance of adherence to warfarin regimen for prevention of thromboembolic events (i.e., not to self-adjust dose around menses) and when to seek medical attention for bleeding.

▪ Refer to progestin-containing products as “hormonal treatments to control heavy menses” instead of solely describing them as “contraceptive” products.

▪ Prevention of Medication-induced Birth Defects

o Warfarin is a known teratogen and can cause birth defects when used by pregnant women.

o The most effective reversible contraceptives are the etonogestrel implant (Implanon) and levonorgestrel-containing IUD (Mirena). These methods have very high rates of user satisfaction and continuation[xiii] and should be considered first line options for women treated with warfarin. These options are available to female Veterans through the Prosthetics department (not Pharmacy).

o Although the copper-bearing IUD is also highly effective, it may increase menstrual flow.

o Although the contraceptive pill, patch, and ring are effective methods of contraception, they require reliable patient adherence to be effective. Since it is difficult for most women to remember to take a pill every day, pregnancy rates with typical use of oral contraceptives are higher than perfect use rates. Progestin-only pills are the most sensitive to missed or late doses.

o The use of combination contraceptive products in patients at increased risk of thromboembolism is controversial. Progestin-only products may be preferable, as current evidence suggests they do not increase thromboembolic risk.4,5,6

o The use of barrier methods (e.g. condoms, diaphragms) as a primary form of contraception is not recommended for women who take warfarin because the failure rate with typical use is unacceptably high for most women.

o Emergency contraceptive pills can be safely used following a contraceptive emergency by women who require anticoagulation.4

▪ Levonorgestrel emergency contraception (Plan B One-Step, Next Choice) is available to women Veterans on VA National Formulary without additional restrictions. Outside VA, levonorgestrel emergency contraception is available without a prescription to those over 16 years of age.

▪ Levonorgestrel emergency contraception is most effective the sooner it is taken after unprotected or inadequately protected intercourse. For this reason, patients should be advised to maintain a supply on hand for immediate use in case a contraceptive emergency arises. However, pills can be used up to 5 days after a contraceptive emergency.

▪ The effectiveness of emergency contraceptive pills may be reduced in the following situations: obesity, delayed treatment beyond 72 hrs, repeated acts of unprotected intercourse, and unprotected intercourse around the time of ovulation.[xiv] Placement of a copper-bearing IUD within 5 days of unprotected intercourse is highly effective as emergency contraception and may be preferred by women in these settings.4

▪ Ulipristal acetate is an alternative oral emergency contraceptive agent newly available by prescription in the US. This agent has not yet been evaluated by the CDC Medical Eligibility Criteria for contraceptive use4 and is not on VA National Formulary. Ulipristal acetate may be more effective for obese women than levonorgestrel pills, though effectiveness of both agents appears to be reduced by obesity.13

Contraceptive Effectiveness Comparison Table

|Selected Contraceptive Methods |Unintended Pregnancy in first year|Women continuing contraceptive use|

| |Typical Use[xv]* |after the first year14,[xvi] |

|Etonogestrel implant (Implanon) |0.05% |83-84% |

|Levonorgestrel IUD (Mirena) |0.2% |80-88% |

|Copper IUD (Paragard) |0.8% |78-84% |

|DMPA injection (Depo-Provera) |3% |56% |

|Pills (combination and progestin-only), patch, ring |8% |55-68% |

|Condoms, male† |15% |68% |

|Condoms, female† |21% |68% |

|No method† |85% |n/a |

*Pregnancy rates among typical couples who initiate use of a method and don’t stop use.

†Not preferred due to high failure rates

o Women currently on warfarin as well as those with a history of VTE who desire pregnancy should establish care with an obstetrician (high-risk specialist if possible) prior to becoming pregnant, whether or not they are currently anticoagulated. One approach to minimize the risk of warfarin-associated embryopathy suggested by the 2008 CHEST Guidelines is to continue warfarin, frequently test for pregnancy, and transition to adjusted dose unfractionated heparin (UFH) or low molecular weight heparin (LMWH) as soon as pregnancy is established.[xvii] Delaying transition from warfarin to UFH/LMWH until pregnancy is established limits the risks and inconveniences of UFH/LMWH until the woman becomes pregnant. Women using this approach should have regular menstrual cycles and agree to frequent pregnancy testing. Alternatively, warfarin may be replaced by UFH or LMWH by a high-risk obstetrician prior to attempting conception to avoid warfarin-related embryopathy.[xviii] As delays in conception are common, the duration of injectable anticoagulant use should be limited to a finite period of time, with re-evaluation of appropriateness, in order to limit the inconveniences, risks, and costs of UFH/LMWH.

▪ Prevention of Hemorrhagic Ovarian Cysts

o Hemorrhagic ovarian cysts are estimated to affect 1% of women receiving anticoagulation medications.3 Hormonal treatments may be used to suppress ovulation and formation of ovarian cysts.

o Progestin-only methods which consistently suppress ovulation include the etonogestrel implant and DMPA.

o Combined (containing an estrogen plus progestin) hormonal pills, patch, or ring will also suppress ovulation, though the use of combination products in patients at increased risk of thromboembolism is controversial.[xix]

o The levonorgestrel IUD and progestin-only pills suppress ovulation for some, but not all, women.[xx],[xxi]

o Hemorrhagic ovarian cysts occur more frequently when INR >4.3

Suggestions to promote high quality care for women Veterans on anticoagulation at the local level:

▪ Inform and educate providers and support personnel (e.g., anticoagulation providers, primary care providers, nursing, support staff, etc.) that women Veterans on anticoagulation face unique issues.

▪ Local leadership should promote effective communication between anticoagulation providers, primary care, women’s health providers, and others as needed.

o Staff should understand what services and options are readily available at the local medical center for treatment of women Veterans.

o Staff should be familiar with when and who to refer for additional care.

o Women Veterans interested in being further evaluated for control of heavy menses and/or effective contraceptive options should be referred in a smooth and timely fashion.

▪ Clinicians monitoring anticoagulation therapy should discuss with patients the unique issues with warfarin treatment in women of reproductive age (contraceptive choices, treatment of heavy menses, teratogenic potential).

References:

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[i]. Huq FY, Tvarkova K, Arafa A, Kadir RA. Menstrual problems and contraception in women of reproductive age receiving oral anticoagulation. Contraception. 2011;84(2):128-32.

[ii]. Dilli D, O[pic]uz S, Dilmen U. A ca K, Arafa A, Kadir RA. Menstrual problems and contraception in women of reproductive age receiving oral anticoagulation. Contraception. 2011;84(2):128-32.

[iii]. Dilli D, Oğuz S, Dilmen U. A case of congenital warfarin syndrome due to maternal drug administration during the pregnancy. Genet Couns. 2011;22(2):221-6.

[iv]. Yamakami LY, de Araujo DB, Silva CA, et al. Severe hemorrhagic corpus luteum complicating anticoagulation in antiphospholipid syndrome. Lupus. 2011 Apr;20(5):523-6.

[v]. Coumarin Derivatives. In: Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 8th ed. Baltimore: Wolters Kluwer-Lippincott Williams and Wilkins; 2008:431-37.

[vi]. Centers for Disease Control and Prevention. US Medical Eligibility Criteria for Contraceptive Use. MMWR Early Release 2010;59:1-86.

[vii]. Lidegaard O, Nielson LH, Skovlund CV, et al. BMJ. 2011; Oct 25;343:d6423.

[viii]. Vaillant-Roussel H, Ouchchane L, Dauphin C, et al. Risk factors for recurrence of venous thromboembolism associated with the use of oral contraceptives. Contraception. 2011;84(5):e23-30.

[ix]. Kaunitz AM, Bissonnette F, Monteiro I, et al. Levonorgestrel-releasing intrauterine system or medroxyprogesterone for heavy menstrual bleeding: a randomized controlled trial. Obstet Gynecol. 2010 Sep;116(3):625-32.

[x]. Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding.Cochrane Database Syst Rev. 2005 Oct 19;(4):CD002126.

[xi]. Bhattacharya S, Middleton LJ, Tsourapas A, Lee AJ, Champaneria R, Daniels JP, et al. Hysterectomy, endometrial ablation and Mirena® for heavy menstrual bleeding: a systematic review of clinical effectiveness and cost-effectiveness analysis. Health Technol Assess 2011;15(19).

[xii]. Culwell KR, Curtis KM. Use of contraceptive methods by women with current venous thrombosis on anticoagulant therapy: a systematic review. Contraception. 2009 Oct;80(4):337-45.

[xiii]. Pisoni CN, Cuadrado MJ, Khamashta MA et al. Treatment of menorrhagia associated with oral anticoagulation: efficacy and safety of the levonorgestrel releasing intrauterine device (Mirena coil). Lupus 2006; 15 (12):877-80.

[xiv]. Peipert JF, Zhao Q, Allsworth JE, et al. Continuation and satisfaction of reversible contraception. Obstet Gynecol. 2011 May;117(5):1105-13.

[xv]. Glasier A, Cameron ST, Blithe D, et al. Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel. Contraception. 2011 Oct;84(4):363-7.

[xvi]. Trussell J. Contraceptive efficacy. In Hatcher RA, Trussell J, Nelson AL, Cates W, Stewart FH, Kowal D. Contraceptive Technology: Nineteenth Revised Edition. New York NY: Ardent Media, 2007.

[xvii]. Peipert JF, Zhao Q, Allsworth JE, et al. Continuation and satisfaction of reversible contraception. Obstet Gynecol. 2011 May;117(5):1105-13.

[xviii]. Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. CHEST. 2008;133(6):844S – 886S.

[xix]. Centers for Disease Control CDC/ATSDR Preconception Care Work Group and the Select Panel on Preconception Care. Recommendations to improve preconception health and healthcare – United States. MMWR. 2006;55:RR-6. Accessed at: . Accessed on December 9, 2011.

[xx]. Trenor CC 3rd, Chung RJ, Michelson AD, et al. Hormonal contraception and thrombotic risk: a multidisciplinary approach. Pediatrics. 2011 Feb;127(2):347-57.

[xxi]. Barbosa I, Olsson SE, Odlind V, et al. Ovarian function after seven years' use of a levonorgestrel IUD. Adv Contracept. 1995 Jun;11(2):85-95.

[xxii]. Endrikat J, Gerlinger C, Richard S, et al. Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide. Contraception. 2011;84:549-57.

Prepared by: Eleanor Bimla Schwarz, MD, MS, University of Pittsburgh and Lisa Longo, PharmD, BCPS, VA PBM Services

Contact: Lisa Longo, PharmD, BCPS, VA PBM Services

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