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Cancer and contraception

      Abstract

      As a result of advances in cancer diagnosis and treatment, young women within the reproductive-aged group are now more likely to survive cancer. Reproductive-aged women with cancer may be interested in deferring pregnancy either temporarily or permanently at cancer diagnosis, during therapy or after treatment. Currently, there are limited guidelines to aide clinicians in managing the contraceptive needs in this special population. After reviewing the evidence regarding the safety and efficacy of available methods of contraception for women who have been diagnosed with cancer, the Society of Family Planning recommends that women of childbearing age who are being treated for cancer avoid combined hormonal contraceptive methods (containing estrogen and progestin) when possible because they may further increase the risk of venous thromboembolism (VTE) (Level A). The copper T380A intrauterine device, a highly effective, reversible, long-acting, hormone-free method, should be considered the first-line contraceptive option for women with a history of breast cancer (Level A), although for women being treated with tamoxifen, the levonorgestrel-containing intrauterine system (IUS) which decreases endometrial proliferation may be preferable (Level B). Women who develop anemia may benefit from use of a progestin-containing contraceptive (Level A). Women who develop osteopenia or osteoporosis following chemotherapy should avoid the progestin-only contraceptive injection (Level B).
      More information is needed in many areas. There are insufficient data to evaluate the risk of VTE when progestin-only contraceptives are used by women at high risk of VTE. Information is also needed on whether the levonorgestrel-containing IUS affects the risk of breast cancer recurrence and whether hormonal contraceptives affect the risk of breast cancer among women who have received chest wall, or “mantle field,” radiation. Finally, studies of the safety and effectiveness of IUS use by women who are immunosuppressed and studies of whether progestin-only contraceptives affect the risk of fracture among cancer survivors or, more generally, women with osteopenia would be useful.

      Keywords

      Background

      Each year in the United States, an estimated 740,000 women are diagnosed with cancer [
      • Jemal A.
      • Siegel R.
      • Xu J.
      • Ward E.
      Cancer statistics, 2010.
      ]. It is now estimated that there are 11.4 million cancer survivors in the United States [
      ], and the number of cancer survivors is likely to grow. Screening allows earlier detection of cancer, and new treatments improve survival. Indeed, 80% of women diagnosed with cancer before the age of 50 years will survive for at least 5 years [
      • (US) NIH
      ]. Unfortunately, many women who have survived cancer continue to feel their reproductive health needs are unmet [
      • Hordern A.
      Intimacy and sexuality after cancer: a critical review of the literature.
      ,
      • Hordern A.J.
      • Street A.F.
      Let's talk about sex: risky business for cancer and palliative care clinicians.
      ]. Cancer survivors have been found to have limited awareness of available contraceptives [
      • Mitwally M.F.
      Management of reproductive needs in cancer patients: clinical perspectives.
      ], in part because many cancer units, including those that care for adolescents, do not routinely discuss contraception with their sexually active patients [
      • Laurence V.
      • Gbolade B.A.
      • Morgan S.J.
      • Glaser A.
      Contraception for teenagers and young adults with cancer.
      ]. Population-representative data on the prevalence of unintended pregnancy among cancer survivors are not currently available. However, in the United States, cancer survivors aged 15–30 were more likely to terminate a pregnancy than age-matched controls [
      • Green D.M.
      • Whitton J.A.
      • Stovall M.
      • et al.
      Pregnancy outcome of female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.
      ]. Similarly, a recent Danish study found that cancer survivors were slightly more likely to terminate a pregnancy than their sisters or population-based controls [
      • Winther J.F.
      • Boice Jr., J.D.
      • Svendsen A.L.
      • Frederiksen K.
      • Olsen J.H.
      Induced abortions in Danish cancer survivors: a population-based cohort study.
      ].
      Contraception is key to preventing unintended pregnancy. However, all contraception is not the same. The World Health Organization has classified contraception into four tiers based on efficacy. Long-acting contraceptive methods including sterilization, implants and intrauterine devices (IUDs) are ranked as the most effective methods (tier 1). Other short-term contraceptive methods, which include combined estrogen and progestin methods with various delivery systems (tier 2) and barrier (tier 3) and behavioral methods (tier 4), may be suboptimal for cancer patients due to decreased efficacy and compliance or hormones which may be relatively or absolutely contraindicated in cancer patients [
      • Steiner M.J.
      • Trussell J.
      • Mehta N.
      • et al.
      Communicating contraceptive effectiveness: a randomized controlled trial to inform a World Health Organization family planning book.
      ].
      While chemotherapy and radiation reduce fertility and may cause ovarian failure [
      • Mitwally M.F.
      Fertility preservation and minimizing reproductive damage in cancer survivors.
      ], many cancer survivors remain fertile [
      • Hodgson D.C.
      • Pintilie M.
      • Gitterman L.
      • et al.
      Fertility among female Hodgkin's lymphoma survivors attempting pregnancy following ABVD chemotherapy.
      ,
      • Partridge A.H.
      • Gelber S.
      • Peppercorn J.
      • et al.
      Fertility and menopausal outcomes in young breast cancer survivors.
      ]. Among childhood cancer survivors, cancer treatment is thought to reduce fertility by 10%–25%, depending on the type of treatment received [
      • Byrne J.
      • Mulvihill J.J.
      • Myers M.H.
      • et al.
      Effects of treatment on fertility in long-term survivors of childhood or adolescent cancer.
      ]. Norwegian data suggest that in the 10 years following a cancer diagnosis, women who are diagnosed with cancer are about half as likely as age-matched women without cancer diagnoses to become pregnant [
      • Cvancarova M.
      • Samuelsen S.O.
      • Magelssen H.
      • Fossa S.D.
      Reproduction rates after cancer treatment: experience from the Norwegian radium hospital.
      ]. However, the fertility of young women treated with gonadotropin-releasing hormone agonists during chemotherapy frequently returns spontaneously after treatment [
      Ethics Committee of the American Society for Reproductive Medicine
      Fertility preservation and reproduction in cancer patients.
      ]. Furthermore, in a study of young survivors of breast cancer, 67% remained fertile [
      • Partridge A.H.
      • Gelber S.
      • Peppercorn J.
      • et al.
      Fertility and menopausal outcomes in young breast cancer survivors.
      ].
      Reproductive-aged, fertile women undergoing cancer treatment are generally advised to avoid pregnancy due to concerns of the teratogenic effects of chemotherapy or radiation. After treatment, many women may choose to prevent pregnancy. And breast cancer survivors are advised to avoid pregnancy for 3 years following cancer treatment [
      • Helewa M.
      • Levesque P.
      • Provencher D.
      • Lea R.H.
      • Rosolowich V.
      • Shapiro H.M.
      Breast cancer, pregnancy, and breastfeeding.
      ] due to concerns that pregnancy-related hormonal changes may increase the risk of recurrence. This guideline has therefore been developed for clinicians caring for reproductive-aged women who need contraceptives after they have been diagnosed with or treated for cancer.
      It is important to explore the patient's understanding of her prognosis, risk of recurrence and fertility, as some women may believe that they are infertile despite resumption of normal menses following treatment for cancer. Uncertainties regarding future fertility, pregnancy outcomes and cancer recurrence can be challenging for patients and their clinicians. At times, the goals of cancer care may conflict with a patient's reproductive goals. However, with appropriate counseling and preventive measures, this conflict may be minimized. Multidisciplinary care involving, as needed, the patient's primary care provider, oncologist, obstetrician and family planning specialist may be helpful in providing individualized recommendations regarding contraception, fertility and pregnancy.

      Clinical questions and recommendations

      How is fertility assessed in cancer survivors? Does this patient need contraception?

      When considering whether a woman who has survived cancer may need contraception, clinicians must be aware that the usual signs of fertility may not be reliable in women who have undergone cancer treatments. Pregnancy has been reported in cancer survivors despite amenorrhea and follicle-stimulating hormone levels suggestive of menopause [
      Ethics Committee of the American Society for Reproductive Medicine
      Fertility preservation and reproduction in cancer patients.
      ,
      • Sklar C.
      Maintenance of ovarian function and risk of premature menopause related to cancer treatment.
      ]. Thus, the absence of menstruation does not necessarily indicate lack of ovarian function [
      • Blumenfeld Z.
      • von Wolff M.
      GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy.
      ]. Since menstrual activity is not a reliable index of ovarian function, various biochemical tests (including follicle-stimulating hormone level, inhibin A or B levels, or anti-Mullerian hormone) and biophysical tests (including vaginal ultrasonography assessment to evaluate antral follicle count and ovarian volume) have been used to estimate ovarian reserve. Currently, anti-Mullerian hormone levels are thought to be the best predictor of a woman's future fertility [
      • Lie Fong S.
      • Laven J.S.
      • Hakvoort-Cammel F.G.
      • et al.
      Assessment of ovarian reserve in adult childhood cancer survivors using anti-Mullerian hormone.
      ,
      • Lutchman Singh K.
      • Davies M.
      • Chatterjee R.
      Fertility in female cancer survivors: pathophysiology, preservation and the role of ovarian reserve testing.
      ,
      • Anderson R.A.
      • Themmen A.P.
      • Al-Qahtani A.
      • Groome N.P.
      • Cameron D.A.
      The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer.
      ]. Identification of which women are fertile after chemotherapy remains an area of active research.

      How does the primary cancer type affect contraceptive options?

      Cancer type influences recommendations regarding contraception. This is especially true for breast cancer or other hormonally mediated cancers. For women with breast cancer, exogenous estrogen and progestins are not recommended due to concerns that they may increase the risk of cancer recurrence. Estrogen and progestin receptor status affect tumor growth and prognosis [
      • Beguelin W.
      • Diaz Flaque M.C.
      • Proietti C.J.
      • et al.
      Progesterone receptor induces ErbB-2 nuclear translocation to promote breast cancer growth via a novel transcriptional effect: ErbB-2 function as a coactivator of Stat3.
      ]; thus, estrogen receptor blockade is a key component of breast cancer treatment. Data are lacking on the extent to which use of estrogen-containing contraceptives by a breast cancer survivor may increase the likelihood of breast cancer recurrence. Additionally, data regarding the impact of postmenopausal hormone replacement therapy are conflicting. Two trials evaluating the use of postmenopausal hormone therapy by breast cancer survivors were stopped early due to safety concerns [
      • Holmberg L.
      • Anderson H.
      HABITS steering and data monitoring committee. HABITS (hormonal replacement therapy after breast cancer — is it safe?), a randomised comparison: trial stopped.
      ,
      • von Schoultz E.
      • Rutqvist L.E.
      Stockholm Breast Cancer Study G. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial.
      ]. In contrast, eight observational studies showed no increased risk of cancer recurrence among breast cancer survivors who took postmenopausal hormone therapy [
      • Col N.F.
      • Kim J.A.
      • Chlebowski R.T.
      Menopausal hormone therapy after breast cancer: a meta-analysis and critical appraisal of the evidence.
      ].
      The role of progestins in breast cancer in both pre- and postmenopausal women remains understudied [
      • Lange C.A.
      • Yee D.
      Progesterone and breast cancer.
      ]. Animal studies have indicated that progestins induce growth and metastasis of breast cancer [
      • Liang Y.
      • Benakanakere I.
      • Besch-Williford C.
      • Hyder R.S.
      • Ellersieck M.R.
      • Hyder S.M.
      Synthetic progestins induce growth and metastasis of BT-474 human breast cancer xenografts in nude mice.
      ,
      • Lanari C.
      • Molinolo A.A.
      Progesterone receptors — animal models and cell signalling in breast cancer. Diverse activation pathways for the progesterone receptor: possible implications for breast biology and cancer.
      ]. Thus, use of systemic progestin-containing contraceptives is generally not advised for women who have a prior diagnosis of breast cancer. Conversely, oral medroxyprogesterone acetate has shown to have some benefit as a chemotherapeutic agent [
      • Chan S.S.
      • Tam W.H.
      • Yeo W.
      • Yu M.M.
      • Ng D.P.
      • Wong A.W.
      • et al.
      A randomised controlled trial of prophylactic levonorgestrel intrauterine system in tamoxifen-treated women.
      ,
      • Gardner F.J.
      • Konje J.C.
      • Abrams K.R.
      • Brown L.J.
      • Khanna S.
      • Al-Azzawi F.
      • et al.
      Endometrial protection from tamoxifen-stimulated changes by a levonorgestrel-releasing intrauterine system: a randomised controlled trial.
      ], and in the general population, progestin-only contraceptives have not been associated with an increased risk of breast cancer [
      • Kesim M.D.
      • Aydin Y.
      • Atis A.
      • Mandiraci G.
      Long-term effects of the levonorgestrel-releasing intrauterine system on serum lipids and the endometrium in breast cancer patients taking tamoxifen.
      ,
      • Trinh X.B.
      • Tjalma W.A.
      • Makar A.P.
      • Buytaert G.
      • Weyler J.
      • van Dam P.A.
      Use of the levonorgestrel-releasing intrauterine system in breast cancer patients.
      ,
      • Gardner F.J.
      • Konje J.C.
      • Bell S.C.
      • et al.
      Prevention of tamoxifen induced endometrial polyps using a levonorgestrel releasing intrauterine system; long-term follow-up of a randomised control trial.
      ,
      • Beex L.
      • Rose C.
      • Mouridsen H.
      • et al.
      Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer: an EORTC Phase III study (10863).
      ,
      • Kloke O.
      • Klaassen U.
      • Oberhoff C.
      • et al.
      Maintenance treatment with medroxyprogesterone acetate in patients with advanced breast cancer responding to chemotherapy: results of a randomized trial. Essen Breast Cancer Study Group.
      ].
      Given the above-mentioned controversies and concerns regarding use of exogenous hormones by women who have been diagnosed with breast cancer, the copper T380A, the most effective hormone-free reversible contraceptive, should be considered the preferred option for breast cancer survivors [
      • Shapiro S.
      • Rosenberg L.
      • Hoffman M.
      • et al.
      Risk of breast cancer in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen contraceptives.
      ,
      Post-marketing surveillance of Norplant((R)) contraceptive implants: II. Non-reproductive health(1).
      ]. Additional studies are needed to evaluate the safety of progestins in hormonally breast cancer, as well as the effect of exogenous hormones on hormonally mediated cancers in premenopausal women.
      For women being treated with tamoxifen, which can cause endometrial proliferation and even endometrial cancer, the levonorgestrel-containing intrauterine system (IUS) may be optimal for both contraceptive and endometrial effects, as it decreases both endometrial proliferation and the need for investigation of vaginal bleeding. While several studies [
      • Strom B.L.
      • Berlin J.A.
      • Weber A.L.
      • et al.
      Absence of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of breast cancer.
      ,
      • Backman T.
      • Rauramo I.
      • Jaakkola K.
      • et al.
      Use of the levonorgestrel-releasing intrauterine system and breast cancer.
      ,
      • Dinger J.
      • Bardenheuer K.
      • Minh T.D.
      Levonorgestrel-releasing and copper intrauterine devices and the risk of breast cancer.
      ,
      • McNaught J.
      • Reid R.L.
      • Provencher D.M.
      • et al.
      Progesterone-only and non-hormonal contraception in the breast cancer survivor: Joint Review and Committee Opinion of the Society of Obstetricians and Gynaecologists of Canada and the Society of Gynecologic Oncologists of Canada.
      ,
      • World Health Organization
      Intrauterine devices in medical eligibility criteria for contraceptive use.
      ] that examined use of the levonorgestrel IUS by women whose breast cancer was being treated with tamoxifen did not find a higher risk of breast cancer recurrence, one subgroup analysis of women who were using a levonorgestrel IUS at the time of breast cancer diagnosis and who continued using their IUS (n=38) found that they were significantly more likely to have a recurrence of breast cancer than women who did not have an IUS at the time they were diagnosed [adjusted hazard ratio, 3.4; 95% confidence interval (CI), 1.01–11.35] [
      • McNaught J.
      • Reid R.L.
      • Provencher D.M.
      • et al.
      Progesterone-only and non-hormonal contraception in the breast cancer survivor: Joint Review and Committee Opinion of the Society of Obstetricians and Gynaecologists of Canada and the Society of Gynecologic Oncologists of Canada.
      ]. More research is therefore needed to determine the long-term safety of the levonorgestrel IUS by women with a history of breast cancer.

      How does the increased risk of venous thromboembolism (VTE) affect contraceptive selection?

      Both cancer [
      • Di Nisio M.
      • Ferrante N.
      • De Tursi M.
      • et al.
      Incidental venous thromboembolism in ambulatory cancer patients receiving chemotherapy.
      ,
      • Khorana A.A.
      • Kuderer N.M.
      • Culakova E.
      • Lyman G.H.
      • Francis C.W.
      Development and validation of a predictive model for chemotherapy-associated thrombosis.
      ] and estrogen [
      • Gomes M.P.
      • Deitcher S.R.
      Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: a clinical review.
      ,
      • Lidegaard O.
      • Edstrom B.
      • Kreiner S.
      Oral contraceptives and venous thromboembolism. A case–control study.
      ] are independent risk factors for VTE. Cancer patients with VTE have twice the mortality of those who do not experience VTE [
      • Sorensen H.T.
      • Mellemkjaer L.
      • Olsen J.H.
      • Baron J.A.
      Prognosis of cancers associated with venous thromboembolism.
      ,
      • Chew H.K.
      • Wun T.
      • Harvey D.
      • Zhou H.
      • White R.H.
      Incidence of venous thromboembolism and its effect on survival among patients with common cancers.
      ]. Indeed, thromboembolism is one of the leading causes of death in cancer patients [
      • Khorana A.A.
      • Francis C.W.
      • Culakova E.
      • Kuderer N.M.
      • Lyman G.H.
      Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy.
      ]. Lung, lymph, gynecologic and genitourinary cancers pose a higher-than-average risk of VTE, and gastric and pancreatic cancers pose a particularly high risk of VTE (i.e., rates are more than three times the population average). In contrast, breast and colorectal cancers are less commonly complicated by VTE [
      • Khorana A.A.
      • Kuderer N.M.
      • Culakova E.
      • Lyman G.H.
      • Francis C.W.
      Development and validation of a predictive model for chemotherapy-associated thrombosis.
      ].
      Due to the increased risk of VTE, the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) recommend that women with active cancer or who have been treated for cancer in the last 6 months (other than nonmelanoma skin cancer) avoid combined hormonal contraceptive methods (Category 4) [
      • Centers for Disease Control and Prevention
      U.S. medical eligibility criteria for contraceptive use, 2010.
      ]. Progestin-only contraceptives increase the risk of VTE much less than estrogen-containing products [
      • Lidegaard O.
      • Lokkegaard E.
      • Svendsen A.L.
      • Agger C.
      Hormonal contraception and risk of venous thromboembolism: national follow-up study.
      ], and the CDC posit that the benefits outweigh the perceived risks (Category 2) [
      • Centers for Disease Control and Prevention
      U.S. medical eligibility criteria for contraceptive use, 2010.
      ].The available literature is insufficient to determine if progestin-only contraceptives increase the likelihood of VTE among high-risk women [
      • Bergendal A.
      • Odlind V.
      • Persson I.
      • Kieler H.
      Limited knowledge on progestogen-only contraception and risk of venous thromboembolism.
      ]. Of several case–control studies that have examined the association between progestin-only contraceptives and VTE, only one found a significantly increased VTE risk [
      • Lidegaard O.
      • Edstrom B.
      • Kreiner S.
      Oral contraceptives and venous thromboembolism. A case–control study.
      ,
      • Lidegaard O.
      • Lokkegaard E.
      • Svendsen A.L.
      • Agger C.
      Hormonal contraception and risk of venous thromboembolism: national follow-up study.
      ,
      World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception
      Cardiovascular disease and use of oral and injectable progestogen-only contraceptives and combined injectable contraceptives. Results of an international, multicenter, case–control study.
      ,
      • Heinemann L.A.
      • Assmann A.
      • DoMinh T.
      • Garbe E.
      Oral progestogen-only contraceptives and cardiovascular risk: results from the Transnational Study on Oral Contraceptives and the Health of Young Women.
      ,
      • Lewis M.A.
      • Heinemann L.A.
      • MacRae K.D.
      • Bruppacher R.
      • Spitzer W.O.
      The increased risk of venous thromboembolism and the use of third generation progestagens: role of bias in observational research. The Transnational Research Group on Oral Contraceptives and the Health of Young Women.
      ,
      • Lidegaard O.
      • Edstrom B.
      • Kreiner S.
      Oral contraceptives and venous thromboembolism: a five-year national case-control study.
      ,
      • Poulter N.R.
      • Chang C.L.
      • Farley T.M.
      • Meirik O.
      Risk of cardiovascular diseases associated with oral progestagen preparations with therapeutic indications.
      ,
      • Vasilakis C.
      • Jick H.
      • del Mar Melero-Montes M.
      Risk of idiopathic venous thromboembolism in users of progestagens alone.
      ,
      • Barsoum M.K.
      • Heit J.A.
      • Ashrani A.A.
      • Leibson C.L.
      • Petterson T.M.
      • Bailey K.R.
      Is progestin an independent risk factor for incident venous thromboembolism? A population-based case–control study.
      ]: A recent report from the Netherlands’ Multiple Environmental and Genetic Assessment of risk factors for VTE case–control study found that women using depot-medroxyprogesterone acetate (DMPA) had a higher risk of VTE than nonusers of hormonal contraception (odds ratio=3.6, 95% CI 1.8–7.1) [
      • van Hylckama Vlieg A.
      • Helmerhorst F.M.
      • Rosendaal F.R.
      The risk of deep venous thrombosis associated with injectable depot-medroxyprogesterone acetate contraceptives or a levonorgestrel intrauterine device.
      ]. Concern has also been raised by older studies of progestin doses higher than those used for contraception which showed an increased risk of VTE among progestin users than among age-matched controls who were not using progestin [
      • Poulter N.R.
      • Chang C.L.
      • Farley T.M.
      • Meirik O.
      Risk of cardiovascular diseases associated with oral progestagen preparations with therapeutic indications.
      ,
      • Vasilakis C.
      • Jick H.
      • del Mar Melero-Montes M.
      Risk of idiopathic venous thromboembolism in users of progestagens alone.
      ]. In general, the available data do not demonstrate that progestin-only contraceptives increase the risk of VTE [
      • Lidegaard O.
      • Lokkegaard E.
      • Svendsen A.L.
      • Agger C.
      Hormonal contraception and risk of venous thromboembolism: national follow-up study.
      ,
      • Darney P.
      • Patel A.
      • Rosen K.
      • Shapiro L.S.
      • Kaunitz A.M.
      Safety and efficacy of a single-rod etonogestrel implant (Implanon): results from 11 international clinical trials.
      ].

      How do common complications of cancer treatment impact contraceptive selection?

      Anemia

      For women affected by anemia, use of hormonal contraceptives for their noncontraceptive benefits may be warranted. Rates of anemia are particularly high for women with lung cancer (77% of whom develop anemia) and gynecologic cancer (81% of whom develop anemia) [
      • Ludwig H.
      • Van Belle S.
      • Barrett-Lee P.
      • et al.
      The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients.
      ]. As women with cancer-induced anemia have decreased functional capacity and quality of life and shorter survival, efforts to minimize menstrual blood loss with the use of a progestin-containing contraceptive [
      • Task Force for Epidemiological Research on Reproductive Health, United Nations Development Programme/United Nations Population Fund/World Health Organization/World Bank Special Programme of Research, Development and Research Training in Human Reproduction
      Effects of contraceptives on hemoglobin and ferritin.
      ], particularly the levonorgestrel IUS [

      Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2005:CD002126. Epub 2005/10/20 (Evidence Grade: I).

      ], may be warranted. The copper T380A may increase menstrual blood loss in some women [
      • Hubacher D.
      • Reyes V.
      • Lillo S.
      • et al.
      Preventing copper intrauterine device removals due to side effects among first-time users: randomized trial to study the effect of prophylactic ibuprofen.
      ], and the implant can cause an unpredictable bleeding profile throughout the course of its use [
      • Affandi B.
      An integrated analysis of vaginal bleeding patterns in clinical trials of Implanon.
      ]. While the clinical implications of these changes in bleeding patterns are unknown, use of other methods of contraception may be advisable in women with severe anemia, particularly if other methods may improve hematologic status.

      Osteoporosis

      Osteoporosis is a common complication of chemotherapy [
      • Reid D.M.
      • Doughty J.
      • Eastell R.
      • et al.
      Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group.
      ,
      • Ramaswamy B.
      • Shapiro C.L.
      Osteopenia and osteoporosis in women with breast cancer.
      ]. For patients with preexisting bone loss, the use of DMPA should be considered with caution; however, the effects of DMPA on bone mineral density have been found to be reversible [
      • Gai L.
      • Zhang J.
      • Zhang H.
      • Gai P.
      • Zhou L.
      • Liu Y.
      The effect of depot medroxyprogesterone acetate (DMPA) on bone mineral density (BMD) and evaluating changes in BMD after discontinuation of DMPA in Chinese women of reproductive age.
      ]. One database study conducted in the general population in the United Kingdom demonstrated that DMPA use was associated with a slight increase in the risk of fracture; this association was not seen in a systematic review of randomized controlled trials of contraception and fracture [
      • Meier C.
      • Brauchli Y.B.
      • Jick S.S.
      • Kraenzlin M.E.
      • Meier C.R.
      Use of depot medroxyprogesterone acetate and fracture risk.
      ,
      • Lopez L.M.
      • Grimes D.A.
      • Schulz K.F.
      • Curtis K.M.
      Steroidal contraceptives: effect on bone fractures in women.
      ,
      • Vestergaard P.
      • Rejnmark L.
      • Mosekilde L.
      The effects of depot medroxyprogesterone acetate and intrauterine device use on fracture risk in Danish women.
      ]. However at present, there are limited data regarding use of DMPA by women with multiple risk factors for osteoporotic fracture [
      • Watson K.C.
      • Lentz M.J.
      • Cain K.C.
      Associations between fracture incidence and use of depot medroxyprogesterone acetate and anti-epileptic drugs in women with developmental disabilities.
      ]. Contraceptive implants have been shown to affect radial [
      • Pongsatha S.
      • Ekmahachai M.
      • Suntornlimsiri N.
      • Morakote N.
      • Chaovisitsaree S.
      Bone mineral density in women using the subdermal contraceptive implant Implanon for at least 2 years.
      ,
      • Monteiro-Dantas C.
      • Espejo-Arce X.
      • Lui-Filho J.F.
      • Fernandes A.M.
      • Monteiro I.
      • Bahamondes L.
      A three-year longitudinal evaluation of the forearm bone density of users of etonogestrel- and levonorgestrel-releasing contraceptive implants.
      ] and ulnar bone mineral density [
      • Bahamondes L.
      • Monteiro-Dantas C.
      • Espejo-Arce X.
      • et al.
      A prospective study of the forearm bone density of users of etonorgestrel- and levonorgestrel-releasing contraceptive implants.
      ]; however, whether this finding is associated with an increased risk of fractures is unknown. The levonorgestrel IUS does not adversely affect bone mineral density [
      • Bahamondes M.V.
      • Monteiro I.
      • Castro S.
      • Espejo-Arce X.
      • Bahamondes L.
      Prospective study of the forearm bone mineral density of long-term users of the levonorgestrel-releasing intrauterine system.
      ]. In contrast, estrogen-containing contraceptives may be advantageous for women who are osteopenic, but study results are mixed [
      • Bhalla A.K.
      Management of osteoporosis in a pre-menopausal woman.
      ,
      • Sim L.A.
      • McGovern L.
      • Elamin M.B.
      • Swiglo B.A.
      • Erwin P.J.
      • Montori V.M.
      Effect on bone health of estrogen preparations in premenopausal women with anorexia nervosa: a systematic review and meta-analyses.
      ].

      Immunosuppression

      There are limited data on IUD use by women with immunosuppression due to cancer treatment. However, the WHO and the CDC state that IUDs can be used safely by these women [
      • Centers for Disease Control and Prevention
      U.S. medical eligibility criteria for contraceptive use, 2010.
      ]. Their recommendations are based on studies assessing IUD use among HIV-positive women, which found that pelvic inflammatory disease and contraceptive failure are rare and that no increased risk for overall complications or infection is observed [
      • Morrison C.S.
      • Sekadde-Kigondu C.
      • Sinei S.K.
      • Weiner D.H.
      • Kwok C.
      • Kokonya D.
      Is the intrauterine device appropriate contraception for HIV-1-infected women?.
      ,
      • Sinei S.K.
      • Morrison C.S.
      • Sekadde-Kigondu C.
      • Allen M.
      • Kokonya D.
      Complications of use of intrauterine devices among HIV-1-infected women.
      ,
      • Stringer E.M.
      • Kaseba C.
      • Levy J.
      • et al.
      A randomized trial of the intrauterine contraceptive device vs hormonal contraception in women who are infected with the human immunodeficiency virus.
      ,
      • Curtis K.M.
      • Nanda K.
      • Kapp N.
      Safety of hormonal and intrauterine methods of contraception for women with HIV/AIDS: a systematic review.
      ]. The limited data on use of IUDs by immunosuppressed women with systemic lupus erythematosus have been reassuring with regards to infection risk. However, the sparse data on use of IUDs by immunosuppressed women who have undergone renal transplant are limited to four case reports with inconsistent results including beneficial effects [
      • Fong Y.F.
      • Singh K.
      Effect of the levonorgestrel-releasing intrauterine system on uterine myomas in a renal transplant patient.
      ], concerns of infection [
      • Paulen M.E.
      • Folger S.G.
      • Curtis K.M.
      • Jamieson D.J.
      Contraceptive use among solid organ transplant patients: a systematic review.
      ] and contraceptive failure [
      • Zerner J.
      • Doil K.L.
      • Drewry J.
      • Leeber D.A.
      Intrauterine contraceptive device failures in renal transplant patients.
      ]. Thus, further study is needed of the use of IUDs by women with immunosuppression or undergoing chemotherapy.

      Radiation to the chest

      Women who have been treated with radiation to the chest (e.g., “mantle field” radiation, which was previously a common treatment for Hodgkin's lymphoma) have an increased risk of developing breast cancer [
      • Sanna G.
      • Lorizzo K.
      • Rotmensz N.
      • et al.
      Breast cancer in Hodgkin's disease and non-Hodgkin's lymphoma survivors.
      ,
      • Meadows A.T.
      • Friedman D.L.
      • Neglia J.P.
      • et al.
      Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort.
      ,
      • Nathan P.C.
      • Ness K.K.
      • Mahoney M.C.
      • et al.
      Screening and surveillance for second malignant neoplasms in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.
      ,
      • Hodgson D.C.
      • Koh E.S.
      • Tran T.H.
      • et al.
      Individualized estimates of second cancer risks after contemporary radiation therapy for Hodgkin's lymphoma.
      ] and thus may want to avoid the potential risks of exogenous estrogen or progestin. However, some clinicians may consider use of modern combined hormonal contraceptives containing low doses of estrogen or use of progestin-only contraceptives acceptable for women who have received chest wall radiation because these methods have not been associated with an increased risk of breast cancer. Nonetheless, the copper T380A IUD is considered the first choice among reversible contraceptives for women who have received chest wall radiation, with the levonorgestrel-containing IUS, which produces the lowest serum hormone levels [
      • Xiao B.L.
      • Zhou L.Y.
      • Zhang X.L.
      • Jia M.C.
      • Luukkainen T.
      • Allonen H.
      Pharmacokinetic and pharmacodynamic studies of levonorgestrel-releasing intrauterine device.
      ,
      • Nilsson C.G.
      • Lahteenmaki P.L.
      • Luukkainen T.
      • Robertson D.N.
      Sustained intrauterine release of levonorgestrel over five years.
      ], as the second choice.

      Do contraceptives affect women's risk of developing cancer?

      Concerns that oral contraceptives may increase risk of breast cancer are based on a 1996 collaborative reanalysis of 54 studies that found that women who were generally taking older combined hormonal contraceptives containing higher doses of estrogen (or who had used such oral contraceptives in the prior 10 years) had a relative risk of breast cancer of 1.24 (95% CI 1.15–1.33) [
      Collaborative Group on Hormonal Factors in Breast Cancer
      Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies.
      ]. However, three recent studies found no association between use of modern oral contraceptives and an increase risk of breast cancer development [
      • Rosenblatt K.A.
      • Gao D.L.
      • Ray R.M.
      • et al.
      Oral contraceptives and the risk of all cancers combined and site-specific cancers in Shanghai.
      ,
      • Marchbanks P.A.
      • McDonald J.A.
      • Wilson H.G.
      • et al.
      Oral contraceptives and the risk of breast cancer.
      ,
      • Vessey M.
      • Yeates D.
      • Flynn S.
      Factors affecting mortality in a large cohort study with special reference to oral contraceptive use.
      ]. Furthermore, previous oral contraceptive use has not been shown to effect either all-cause or breast-cancer-specific mortality among women with invasive breast cancer [
      • Wingo P.A.
      • Austin H.
      • Marchbanks P.A.
      • Whiteman M.K.
      • Hsia J.
      • Mandel M.G.
      • et al.
      Oral contraceptives and the risk of death from breast cancer.
      ,
      • Lu Y.
      • Ma H.
      • Malone K.E.
      • Norman S.A.
      • Sullivan-Halley J.
      • Strom B.L.
      • et al.
      Oral contraceptive use and survival in women with invasive breast cancer.
      ].
      In the general population, the levonorgestrel IUS has not been shown to increase the risk of breast cancer [
      • Backman T.
      • Rauramo I.
      • Jaakkola K.
      • et al.
      Use of the levonorgestrel-releasing intrauterine system and breast cancer.
      ,
      • Dinger J.
      • Bardenheuer K.
      • Minh T.D.
      Levonorgestrel-releasing and copper intrauterine devices and the risk of breast cancer.
      ]. Similarly, use of injectable and implantable progestin-only contraceptives [
      • Shapiro S.
      • Rosenberg L.
      • Hoffman M.
      • et al.
      Risk of breast cancer in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen contraceptives.
      ,
      • Strom B.L.
      • Berlin J.A.
      • Weber A.L.
      • et al.
      Absence of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of breast cancer.
      ] has not been associated with an increased risk of breast cancer.
      Although ovarian and endometrial cancers are hormonally mediated, the use of progestin-containing contraceptives (whether or not they contain estrogen) actually reduces the risk of these cancers [
      • Vessey M.
      • Yeates D.
      • Flynn S.
      Factors affecting mortality in a large cohort study with special reference to oral contraceptive use.
      ,
      • Wingo P.A.
      • Austin H.
      • Marchbanks P.A.
      • Whiteman M.K.
      • Hsia J.
      • Mandel M.G.
      • et al.
      Oral contraceptives and the risk of death from breast cancer.
      ,
      • Lu Y.
      • Ma H.
      • Malone K.E.
      • Norman S.A.
      • Sullivan-Halley J.
      • Strom B.L.
      • et al.
      Oral contraceptive use and survival in women with invasive breast cancer.
      ,
      • Kumle M.
      • Weiderpass E.
      • Braaten T.
      • Norwegian-Swedish Women's Lifestyle and Health Cohort Study
      • et al.
      Risk for invasive and borderline epithelial ovarian neoplasias following use of hormonal contraceptives: the Norwegian–Swedish Women's Lifestyle and Health Cohort Study.
      ,
      • Beral V.
      • Doll R.
      • Hermon C.
      • Peto R.
      • Reeves G.
      Collaborative Group on Epidemiological Studies of Ovarian Cancer
      Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls.
      ,
      • Dossus L.
      • Allen N.
      • Kaaks R.
      • et al.
      Reproductive risk factors and endometrial cancer: the European Prospective Investigation into Cancer and Nutrition.
      ,
      • Kim J.J.
      • Chapman-Davis E.
      Role of progesterone in endometrial cancer.
      ]. Similarly, use of either the copper T380A IUD or the levonorgestrel IUS appears to reduce risk of endometrial cancer [
      • Buttini M.J.
      • Jordan S.J.
      • Webb P.M.
      The effect of the levonorgestrel-releasing intrauterine system on endometrial hyperplasia: an Australian study and systematic review.
      ,
      • Curtis K.M.
      • Marchbanks P.A.
      • Peterson H.B.
      Neoplasia with use of intrauterine devices.
      ]. However, findings on whether the levonorgestrel IUS affects the risk of ovarian cancer are inconsistent [
      • Ness R.B.
      • Dodge R.C.
      • Edwards R.P.
      • Baker J.A.
      • Moysich K.B.
      Contraception methods, beyond oral contraceptives and tubal ligation, and risk of ovarian cancer.
      ,
      • Tworoger S.S.
      • Fairfield K.M.
      • Colditz G.A.
      • Rosner B.A.
      • Hankinson S.E.
      Association of oral contraceptive use, other contraceptive methods, and infertility with ovarian cancer risk.
      ,
      • Dorjgochoo T.
      • Shu X.O.
      • et al.
      Use of oral contraceptives, intrauterine devices and tubal sterilization and cancer risk in a large prospective study, from 1996 to 2006.
      ,
      • Zapata L.B.
      • Whiteman M.K.
      • Marchbanks P.A.
      • Curtis K.M.
      Intrauterine device use among women with ovarian cancer: a systematic review.
      ], and when ovarian cancer is a concern (e.g., for women who are BRCA1 and BRCA2 carriers) [
      • Iodice S.
      • Barile M.
      • Rotmensz N.
      • et al.
      Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis.
      ,
      • Gadducci A.
      • Biglia N.
      • Cosio S.
      • Sismondi P.
      • Genazzani A.R.
      Gynaecologic challenging issues in the management of BRCA mutation carriers: oral contraceptives, prophylactic salpingo-oophorectomy and hormone replacement therapy.
      ], systemic levels of progestin that suppress ovulation are preferable to intrauterine or barrier methods of contraception.

      Is emergency contraception safe for women with cancer?

      There are no studies in the current body of literature to address the use of the emergency contraceptive pill in women with cancer or who have undergone cancer therapy. The CDC postulates that emergency contraceptive pills have fewer clinical repercussions than combined oral contraceptives or progestin-only contraceptives as the duration of use is shorter. However, it is unknown how frequent repeated use of emergency contraceptive pills would affect women with cancer who may be advised to avoid other hormonal contraceptive methods. Certainly, use of the copper T380A IUD is safe and effective for both emergency contraception and continued use for birth control in these women.

      Conclusions and recommendations

      All women seeking contraception should be provided with information about the relative effectiveness of available contraceptives with typical use. For most women who are being treated for cancer, highly effective reversible contraceptives, such as intrauterine or implantable contraceptives, are recommended. For women who have been cancer-free for at least 6 months and have no history of hormonally mediated cancers, chest wall irradiation, anemia, osteoporosis or VTE, the use of any method of contraception can be recommended.
      The following recommendations are based on good and consistent scientific evidence (Level A):
      • Combined hormonal contraceptive methods (containing estrogen and progestin) should be avoided by women with active cancer or who have been treated for cancer in the last 6 months due to the increased risk of VTE.
      • For women with a history of breast cancer, the copper T380A IUD, a highly effective, hormone-free method, is recommended.
      • For women with anemia, the levonorgestrel-containing IUS may be used to minimize menstrual blood loss.
      The following recommendations are based on limited or inconsistent scientific evidence (Level B):
      • For women with breast cancer treated with tamoxifen, the levonorgestrel-containing IUS provides highly effective contraception and reduces tamoxifen-induced endometrial changes without increasing the risk of breast cancer recurrence.
      • For women with a history of chest wall irradiation, systemic estrogen and progestin should be avoided.
      • Women with osteopenia or osteoporosis should avoid injectable progestin-only contraceptives.
      • Estrogen-containing contraception may be beneficial to women with osteopenia or osteoporosis.
      • Women with immunosuppression may safely use intrauterine contraception.
      • Emergency contraceptive pills may be used by women at risk of breast cancer or breast cancer recurrence who decline emergency placement of a copper T380A IUD.

      Important questions to be answered

      Further study of a number of issues would be useful to clinicians providing contraceptive care to women with a history of cancer. In particular, there is a need for well-designed studies with sufficient statistical power to evaluate risks of VTE when progestin-only contraceptives are used by women at high risk of VTE. More data are needed on the effect of the levonorgestrel-containing IUS on breast cancer recurrence risk and the effects of hormonal contraception on risk of breast cancer among women who have received chest wall radiation. Finally, studies of the effect of progestin-only contraceptives on risk of fracture among cancer survivors or, more generally, women with osteopenia and studies of the safety and effectiveness of IUS use by women with immunosuppression would be useful.

      Sources

      PUBMED and Google Scholar were searched in English for publications regarding contraception and cancer. In addition, reference lists of identified manuscripts were searched for any additional studies that might be relevant. We also searched the Cochrane Clinical Register of Controlled Trials and clinicaltrials.gov, although randomized trials in this area are challenging to perform.

      Authorship

      These guidelines were prepared by Ashlesha Patel, M.D., M.P.H., with assistance from Alicia Roston, M.P.H., and E. Bimla Schwarz, M.D., M.S., and were reviewed by the Board of the Society of Family Planning.

      Conflict of interest

      Ashlesha Patel, MD, MPH; Mini Sreedevi, MD; E. Bimla Schwarz, MD, MS; and Alicia Roston, MPH, report no significant relationship with industry relative to these guidelines. The Society of Family Planning receives no direct support from pharmaceutical companies or other industries.

      Intended audience

      This Society of Family Planning guideline was developed for its members and other clinicians. This guideline may be of interest to other professional groups that set practice standards for family planning services. The purpose of this document is to review the medical literature regarding cancer and contraception. This evidence-based review should help to guide clinicians providing this care, but it is not intended to dictate clinical care.

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