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Current Issues in Contraception

      Abstract

      Contraceptive management in women should take into account patient lifestyle and coexisting medical issues as well as method safety, efficacy, and noncontraceptive benefits. This review focuses on common and timely issues related to contraception encountered in clinical practice, including migraine headaches and associated risk of ischemic stroke, the use of combined hormonal contraception along with citalopram and escitalopram, contraceptive efficacy and safety in the setting of obesity, contraceptives for treatment of menorrhagia, the association of intrauterine contraception and decreased risk of cervical cancer, and the association of venous thromboembolism and combined hormonal contraception. Recent trends supporting the use of long-acting reversible contraception are also reviewed.

      Abbreviations and Acronyms:

      BMI (body mass index), CDC (Centers for Disease Control and Prevention), CHC (combined estrogen- and progestin-containing hormonal contraception), DMPA (depot medroxyprogesterone acetate contraceptive injection), EC (emergency contraception), FDA (Food and Drug Administration), IUC (intrauterine contraception), LARC (long-acting reversible contraception), MI (myocardial infarction), NSAID (nonsteroidal anti-inflammatory drug), OC (oral contraceptive), VTE (venous thromboembolism)
      CME Activity
      Target Audience: The target audience for Mayo Clinic Proceedings is primarily internal medicine physicians and other clinicians who wish to advance their current knowledge of clinical medicine and who wish to stay abreast of advances in medical research.
      Statement of Need: General internists and primary care physicians must maintain an extensive knowledge base on a wide variety of topics covering all body systems as well as common and uncommon disorders. Mayo Clinic Proceedings aims to leverage the expertise of its authors to help physicians understand best practices in diagnosis and management of conditions encountered in the clinical setting.
      Accreditation: College of Medicine, Mayo Clinic is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
      Credit Statement: College of Medicine, Mayo Clinic designates this journalbased CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s).TM Physicians should claim only the credit commensurate with the extent of their participation in the activity.
      Learning Objectives: On completion of this article, you should be able to (1) describe several contraceptive issues commonly encountered in practice, (2) review best practices relating to these issues, and (3) provide resources and guidance for the selection of contraception for women with common coexisting medical issues.
      Disclosures: As a provider accredited by ACCME, College of Medicine, Mayo Clinic (Mayo School of Continuous Professional Development) must ensure balance, independence, objectivity, and scientific rigor in its educational activities. Course Director(s), Planning Committee members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off-label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so that those participants in the activity may formulate their own judgments regarding the presentation.
      In their editorial and administrative roles, William L. Lanier, Jr, MD, Thomas J. Beckman, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry.
      Drs Marnach, Long, and Casey receive research support from Merck & Co, Inc. Drs Long and Casey are certified Nexplanon trainers who are not paid for training services.
      Method of Participation: In order to claim credit, participants must complete the following:
      • 1.
        Read the activity
      • 2.
        Complete the online CME Test and Evaluation. Participants must achieve a score 80% on the CME Test. One retake is allowed.
      Participants should locate the link to the activity desired at http://bit.ly/Xw8oCd. Upon successful completion of the online test and evaluation, you can instantly download and print your certificate of credit.
      Estimated Time: The estimated time to complete each article is approximately 1 hour.
      Hardware/Software: PC or MAC with internet access.
      Date of Release: 3/1/2013
      Expiration date: 2/28/2015 (Credit can no longer be offered after it has passed the expiration date.)
      Questions? Contact [email protected] .
      Every year in the United States nearly 50% of pregnancies are unintended, and 43% of these end in termination.
      • Finer L.B.
      • Zolna M.R.
      Unintended pregnancy in the United States: incidence and disparities, 2006.
      Therefore, the availability of convenient, effective contraception represents a public health need. The Centers for Disease Control and Prevention (CDC) United States medical eligibility criteria for contraceptive use in women with various medical conditions is based on evaluation of available data and serves as a useful resource for informing contraceptive counseling and selection.
      Centers for Disease Control and Prevention
      U.S. medical eligibility criteria for contraceptive use, 2010: adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed.
      This review focuses on several common issues in contraceptive management.

      What's New in Combined Estrogen- and Progestin-Containing Hormonal Contraception?

      Many women worldwide favor combined estrogen- and progestin-containing hormonal contraception (CHC), which includes pills, patches, and rings with compliance-dependent failure rates reported as 2% to 9% per year.
      Centers for Disease Control and Prevention
      U.S. medical eligibility criteria for contraceptive use, 2010: adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed.
      In comparison, pregnancy rates associated with intrauterine contraception (IUC), the contraceptive implant (progestin-only subcutaneous implant that lasts up to 3 years), injections, and sterilization are lower (<1%) and do not require regular attention.
      American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin No. 121: Long-acting reversible contraception: implants and intrauterine devices.
      Recent trends in CHC have included lower estrogen doses (as low as 10 μg/d), novel compounds (third-generation progestins, drospirenone, and estradiol valerate), and varied oral contraceptive (OC) regimens including shortened hormone-free intervals resulting in shorter, lighter monthly flow and lower risk of ovarian cysts as well as extended and continuous contraceptives associated with 4 or no scheduled menstrual intervals per year.
      • Willis S.A.
      • Kuehl T.J.
      • Spiekerman A.M.
      • Sulak P.J.
      Greater inhibition of the pituitary-ovarian axis in oral contraceptive regimens with a shortened hormone-free interval.
      When using OCs in a continuous or extended fashion, monophasic formulations, which contain 21 identically dosed pills per package, are recommended. This is contrasted with triphasic formulations used for late-cycle breakthrough bleeding, which “step up” the progestin dose each week in order to support the thickening endometrium. Breakthrough bleeding associated with fewer scheduled menstrual intervals generally resolves within a few months.

      Treating Abnormal Uterine Bleeding With Contraception

      Combined estrogen- and progestin-containing hormonal contraceptives, and specifically OCs, have long been used off label to treat heavy menstrual bleeding. A new 28-day OC associated with lower mean blood loss and improved hemoglobin/hematocrit and ferritin levels has received US Food and Drug Administration (FDA) approval for treatment of menorrhagia.
      • Jensen J.T.
      • Parke S.
      • Mellinger U.
      • Machlitt A.
      • Fraser I.S.
      Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: a randomized controlled trial.
      This OC contains 22 days of various combinations of estradiol valerate and dienogest, 4 days of estradiol valerate alone, and 2 days of hormone-free pills.
      Because of reported menstrual blood loss reduction of up to 90% and consequent reduction in the need for operative intervention for abnormal uterine bleeding (menorrhagia), the levonorgestrel intrauterine system has received FDA approval for treatment of menorrhagia and has data supporting its use for dysmenorrhea and endometriosis.
      ACOG Practice Bulletin No. 110: Noncontraceptive uses of hormonal contraceptives.
      It provides contraception for up to 5 years.

      Why Worry About Citalopram (or Escitalopram) and CHC?

      Citalopram has been associated with a prolonged QTc interval that may trigger a life-threatening arrhythmia, torsade de pointes (a form of polymorphic ventricular tachycardia).
      • Vieweg W.V.
      • Hasnain M.
      • Howland R.H.
      • et al.
      Citalopram, QTc interval prolongation, and torsade de pointes: how should we apply the recent FDA ruling?.
      A recent Mayo Clinic consensus statement recommended the following: before prescribing citalopram at 40 mg or higher or escitalopram at 20 mg or higher along with CHC, an electrocardiogram and review of the personal and family history of each patient should be obtained.
      • Sheeler R.D.
      • Ackerman M.J.
      • Richelson E.
      • et al.
      Considerations on safety concerns about citalopram prescribing.
      Alternative contraceptive methods should be discussed with patients taking citalopram or escitalopram plus CHC.

      Contraception, Venous Thromboembolism, and Cardiovascular Risk: Beyond Odds Ratios

      Observational studies have shown a 2- to 7-fold increased risk of venous thromboembolism (VTE) (absolute risk, approximately 1 event per 3500 women) in users of CHC compared with women who do not use CHC.
      • Lidegaard Ø.
      • Løkkegaard E.
      • Svendsen A.L.
      • Agger C.
      Hormonal contraception and risk of venous thromboembolism: national follow-up study.
      Oral contraceptives containing third-generation progestogens (desogestrel, norgestimate, and gestodene) or the progestin drospirenone have a greater risk of VTE (1.5- to 3-fold increased risk over OCs containing levonorgestrel).
      • Jick S.S.
      • Hernandez R.K.
      Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data.
      Although the absolute risk of VTE remains low, women using drospirenone should be counseled regarding potential increased risk. Further, this risk may be higher in users of the contraceptive patch vs users of similar OCs.

      US Food and Drug Administration. Background Document for Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee. NDA 21-180 Ortho Evra. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM282634.pdf. Published December 9, 2011. Accessed December 28, 2012.

      Nonetheless, an FDA Advisory Committee has concluded that the benefits of CHC likely outweigh the risks in most women.

      US Food and Drug Administration. Birth control pills containing drospirenone: label change—products may be associated with higher risk for blood clots. US Food and Drug Administration website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm299605.htm. Updated April 10, 2012. Accessed December 28, 2012.

      The progestin-only contraceptive methods, including the progestin-only pill, depot medroxyprogesterone acetate contraceptive injection (DMPA), and levonorgestrel intrauterine system, do not considerably increase the risk of VTE.
      • Vasilakis C.
      • Jick H.
      • del Mar Melero-Montes M.
      Risk of idiopathic venous thromboembolism in users of progestogens alone.
      Additionally, nonhormonal contraceptive methods, including the copper IUC, diaphragm, cervical cap, condoms, or sterilization, provide alternatives for women at risk for VTE. The World Health Organization does not recommend routine screening for thrombogenic mutations.
      Centers for Disease Control and Prevention
      U.S. medical eligibility criteria for contraceptive use, 2010: adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed.
      Cardiovascular risk or myocardial infarction (MI) with the use of CHC appears to be extremely rare in healthy women of reproductive age. In the largest cohort study to date, Danish women aged 15 to 49 years who were using CHC were followed up for 15 years to evaluate the association of arterial thrombotic risk and the use of 20- to 40-μg ethinyl estradiol OCs; the relative risk of MI was 1.4 to 1.88.
      • Lidegaard Ø.
      • Løkkegaard E.
      • Jensen A.
      • Skovlund C.W.
      • Keiding N.
      Thrombotic stroke and myocardial infarction with hormonal contraception.
      No excess risk was seen for arterial thrombosis (MI or thrombotic stroke) with any of the progestin-only methods.

      The Migraine Conundrum

      Headaches are common in women using CHCs, occasionally more so at initiation of the medication. In this instance, they typically improve with continued use, especially with extended cycles. Types and dosages of progestins do not affect headache risk. Withdrawal of about 20 μg of estradiol triggers migraines, supporting the use of low-dose estradiol-only pills (10 μg) during part of the traditional placebo interval in some monthly and extended-cycle formulations.
      • Shuster L.T.
      • Faubion S.S.
      • Sood R.
      • Casey P.M.
      Hormonal manipulation strategies in the management of menstrual migraine and other hormonally related headaches.
      However, CHC use also confers a 2- to 3-fold independent risk of ischemic stroke in women without migraines.
      • Shuster L.T.
      • Faubion S.S.
      • Sood R.
      • Casey P.M.
      Hormonal manipulation strategies in the management of menstrual migraine and other hormonally related headaches.
      Migraine with aura is further associated with a 6- to 8-fold increased risk of ischemic stroke as compared with migraine without aura. Women who experience migraine without aura have a 2- to 3-fold increased risk of ischemic stroke compared with women without migraine. Data quantifying ischemic stroke risk in CHC users with migraines in the absence and presence of aura is difficult to interpret given differing CHC formulations.
      • Faubion S.S.
      • Casey P.M.
      • Shuster L.T.
      Hormonal contraception and migraine: clinical considerations.
      The risks of CHC usually outweigh the benefits in women older than 35 with migraine.
      Centers for Disease Control and Prevention
      U.S. medical eligibility criteria for contraceptive use, 2010: adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed.
      Alternatives to CHC are recommended for women of any age who have migraine with aura or focal neurologic symptoms.
      Centers for Disease Control and Prevention
      U.S. medical eligibility criteria for contraceptive use, 2010: adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed.

      Contraception for Women With Elevated Body Mass Index

      Much attention has been focused on obesity and contraceptive efficacy. Recent data from the Contraceptive CHOICE Project was reassuring, with a cumulative 3-year pregnancy rate of only 1 in 100 woman-years for the contraceptive implant and IUC regardless of body mass index (BMI) (calculated as the weight in kilograms divided by the height in meters squared).
      • Xu H.
      • Wade J.A.
      • Peipert J.F.
      • Zhao Q.
      • Madden T.
      • Secura G.M.
      Contraceptive failure rates of etonogestrel subdermal implants in overweight and obese women.
      Combined estrogen- and progestin-containing hormonal contraception is deemed second-line contraception by the CDC because of concerns about increasing VTE risk in obese women.
      Centers for Disease Control and Prevention
      U.S. medical eligibility criteria for contraceptive use, 2010: adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed.
      Progestogen-only and nonhormonal contraceptives are preferred methods of contraception for women who are obese. Permanent sterilization using a transcervical hysteroscopic approach is an excellent option for women who have completed childbearing.
      Women with a BMI of more than 30 kg/m2 who need emergency contraception (EC) are better served by administration of ulipristal acetate rather than levonorgestrel EC because of the much lower pregnancy rates associated with ulipristal.
      • Glasier A.
      • Cameron S.T.
      • 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.
      An extremely efficacious EC in all women is the copper IUC placed within 5 days of last intercourse. This device may be retained for primary contraception for up to 10 years.

      Trend Toward Long-Acting Reversible Contraception

      In the Contraceptive CHOICE study,
      • Peipert J.F.
      • Madden T.
      • Allsworth J.E.
      • Secura G.M.
      Preventing unintended pregnancies by providing no-cost contraception.
      more than 9000 women aged 14 to 45 years were given their choice of birth control methods, including OCs, patch, ring (non–long-acting reversible contraception [LARC]), IUC, or implant (LARC) at no cost. Long-acting reversible contraception was the choice in 75% of women (58% choosing IUCs and 17% implants). A 22 to 20-fold lower pregnancy rate was reported in LARC users. Furthermore, pregnancy rates among 15- to 19-year-old women in the CHOICE study were 6.3 per 1000 participants compared with 34.3 per 1000 participants nationally, and abortion rates in the project participants were 4.4 to 7.5 per 1000 participants compared with 19.6 per 1000 participants in similarly aged nonparticipants.
      • Peipert J.F.
      • Madden T.
      • Allsworth J.E.
      • Secura G.M.
      Preventing unintended pregnancies by providing no-cost contraception.
      Long-acting reversible contraception is safe in most women. Of women aged 15 to 19 years, 42% are sexually active, and 82% of adolescent pregnancies are unplanned. The American College of Obstetricians and Gynecologists endorses LARC as a first-line option for adolescents.
      Committee on Adolescent Health Care Long-Acting Reversible Contraception Working Group, The American College of Obstetricians and Gynecologists
      Committee opinion no. 539: Adolescents and long-acting reversible contraception: implants and intrauterine devices.

      Intrauterine Contraception Today

      Current IUC has not been associated with pelvic inflammatory infection or tubal infertility.
      American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin No. 121: Long-acting reversible contraception: implants and intrauterine devices.
      Intrauterine contraceptives can be inserted in most women, including nulliparas, without difficulty. The contraindications to IUC use are few, as noted in the Table. Oral nonsteroidal anti-inflammatory drugs (NSAIDs) are helpful for postprocedural cramping. Sexually transmitted infection screening (chlamydia and gonorrhea) is recommended for women younger than 24 years and older women with risk factors.
      Centers for Disease Control and Prevention
      U.S. medical eligibility criteria for contraceptive use, 2010: adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed.
      American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin No. 121: Long-acting reversible contraception: implants and intrauterine devices.
      The IUC expulsion rate is 3% to 5% in all users and 5% to 22% in adolescents. Prior expulsion is not a contraindication to another IUC placement.
      TableAbsolute Contraindications to Intrauterine Device Insertion
      Data from the Centers for Disease Control and Prevention.
      Centers for Disease Control and Prevention
      U.S. medical eligibility criteria for contraceptive use, 2010: adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed.
      Current pregnancy
      Unexplained vaginal bleeding
      Intrauterine device in the uterus
      Acute pelvic inflammatory disease or intrauterine infection in the past 3 mo
      Distorted endometrial cavity preventing proper placement
      Current endometrial or cervical cancer
      Ongoing elevated human chorionic gonadotropin level with trophoblastic disease
      Mild cramping and irregular bleeding in the first 3 to 6 months after IUC placement may be treated with NSAIDs.
      American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin No. 121: Long-acting reversible contraception: implants and intrauterine devices.
      If heavy bleeding persists, pelvic ultrasonography or office hysteroscopy should be considered for evaluation.

      IUC and Decreased Risk of Cervical Cancer

      In a pooled analysis of 26 studies, IUC has been reported to have an association with lower rates of cervical squamous cell cancers, adenocarcinoma, and adenosquamous cancers.
      • Castellsagué X.
      • Diaz M.
      • Vaccarella S.
      • et al.
      Intrauterine device use, cervical infection with human papillomavirus, and risk of cervical cancer: a pooled analysis of 26 epidemiological studies.
      No association was noted between IUC use and human papillomavirus detection among women without cervical cancer. The possible mechanism for a protective cofactor in cervical carcinogenesis may be cellular immunity triggered by IUC.
      • Castellsagué X.
      • Diaz M.
      • Vaccarella S.
      • et al.
      Intrauterine device use, cervical infection with human papillomavirus, and risk of cervical cancer: a pooled analysis of 26 epidemiological studies.
      This data contrasts with an increased risk of cervical cancer in OC users. Pooled data from 24 studies involving more than 16,000 women showed that the risk of cervical cancer increases with increasing duration of use (relative risk, 1.90 at 5 or more years).
      • Appleby P.
      • Beral V.
      • Berrington de González A.
      • et al.
      International Collaboration of Epidemiological Studies of Cervical Cancer
      Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies.
      The risk decreased after OC use ceased, returning to that of nonusers after 10 years. It remains unclear whether there is a causal relationship between OCs and cervical cancer.

      Etonogestrel Subdermal Implant: The Newest LARC

      The single-rod etonogestrel subdermal implant offers high contraceptive efficacy for up to 3 years with a lower dose of progestin than that with CHC, progestin-only pills, or DMPA. It has a neutral effect on bone density as well as on lactation, thus serving as a long-term alternative for prior DMPA users.
      American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin No. 121: Long-acting reversible contraception: implants and intrauterine devices.
      Bleeding patterns with the implant assessed in 90-day reference periods in 11 international trials included infrequent bleeding in 34% of the reference periods, frequent bleeding in 7%, prolonged bleeding in 18%, and amenorrhea in 22%.
      • Mansour D.
      • Korver T.
      • Marintcheva-Petrova M.
      • Fraser I.S.
      The effects of Implanon on menstrual bleeding patterns.
      In a recent Mayo Clinic study,
      • Casey P.M.
      • Long M.E.
      • Marnach M.L.
      • Bury J.E.
      Bleeding related to etonogestrel subdermal implant in a US population.
      about 14.8% of the participants discontinued the implant because of bleeding. Short-term doxycycline, NSAIDs, CHC, or estradiol have been used for treatment of prolonged bleeding.
      • Weisberg E.
      • Hickey M.
      • Palmer D.
      • et al.
      A randomized controlled trial of treatment options for troublesome uterine bleeding in Implanon users.

      Conclusion

      There are many excellent contraceptive choices today for women across their reproductive lifespan. Women have indicated preference for non–compliance-dependent, highly efficacious LARC methods as well as fewer scheduled menstrual intervals per year with CHC. Long-acting reversible contraception may be the ideal first option for most women, including those with higher BMI, migraine, concurrent citalopram or escitalopram use, or compliance issues. Contraceptive management may be informed by the CDC United States medical eligibility criteria for contraceptive use document.
      Centers for Disease Control and Prevention
      U.S. medical eligibility criteria for contraceptive use, 2010: adapted from the World Health Organization Medical Eligibility Criteria for Contraceptive Use, 4th ed.

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        Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: a randomized controlled trial.
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        Can we identify women at risk of pregnancy despite using emergency contraception? data from randomized trials of ulipristal acetate and levonorgestrel.
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        Preventing unintended pregnancies by providing no-cost contraception.
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        Committee opinion no. 539: Adolescents and long-acting reversible contraception: implants and intrauterine devices.
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        • Vaccarella S.
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        Intrauterine device use, cervical infection with human papillomavirus, and risk of cervical cancer: a pooled analysis of 26 epidemiological studies.
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        • Berrington de González A.
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      Linked Article

      • Emergency Life Prevention
        Mayo Clinic ProceedingsVol. 91Issue 12
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          The recent article on emergency contraception1 and another procontraception article published earlier in the Proceedings2 justify contraception because of the incidence of “unintended” pregnancies, and both cite the same article in support.3 However, the authors do not mention that the article by Finer and Zolna3 clearly documents that the rate of unintended pregnancies actually increased between the years 2001 and 2006 despite years of massive and well-orchestrated promotion of contraception and an 89% user rate.
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      • Contra Contraception
        Mayo Clinic ProceedingsVol. 88Issue 8
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          The recent review article by Marnach et al1 asserts that contraception is a public health need because of the high rate of unintended pregnancies and the high rate of such pregnancies ending through abortion. This assertion is misleading on several fronts. First, “unintended” implies accidental, yet procreative potential is an essential element of the sexual act, not an accidental by-product. It is a disservice to the understanding and volitional capacity of most people who engage in an act inherently procreative to imply that they do not understand the nature of the act or do not exercise free choice when deciding whether or not to engage in it.
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