|Birth control type||Hormonal|
|Pregnancy rates (first year)|
|Perfect use||Varies by method: 0.05-2%|
|Typical use||Varies by method: 0.05-9%|
|User reminders||Must follow usage schedule|
|Clinic review||Every 3-12 months, depending on method|
|Advantages and disadvantages|
|Periods||Frequently lighter, for some methods periods may stop altogether|
|Weight||No proven effect|
Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The original hormonal method—the combined oral contraceptive pill—was first marketed as a contraceptive in 1960. In the ensuing decades many other delivery methods have been developed, although the oral and injectable methods are by far the most popular. Altogether, 18% of the world's contraceptive users rely on hormonal methods. Hormonal contraception is highly effective: when taken on the prescribed schedule, users of steroid hormone methods experience pregnancy rates of less than 1% per year. Perfect-use pregnancy rates for most hormonal contraceptives are usually around the 0.3% rate or less. Currently available methods can only be used by women; the development of a male hormonal contraceptive is an active research area.
There are two main types of hormonal contraceptive formulations: combined methods which contain both an estrogen and a progestin, and progestogen-only methods which contain only progesterone or one of its synthetic analogues (progestins). Combined methods work by suppressing ovulation and thickening cervical mucus; while progestogen-only methods reduce the frequency of ovulation, most of them rely more heavily on changes in cervical mucus. The incidence of certain side effects is different for the different formulations: for example, breakthrough bleeding is much more common with progestogen-only methods. Certain serious complications occasionally caused by estrogen-containing contraceptives are not believed to be caused by progestogen-only formulations: deep vein thrombosis is one example of this.
- 1 Medical uses
- 2 Side-effects
- 3 Types
- 4 Mechanism of action
- 5 Frequency of use
- 6 History
- 7 See also
- 8 Footnotes
Hormonal contraception is primarily used for the prevention of pregnancy, but is also prescribed for the treatment of polycystic ovary syndrome, menstrual disorders such as dysmenorrhea and menorrhagia, and hirsutism.
Polycystic ovary syndrome
Hormonal treatments, such as hormonal contraceptives, are frequently successful at alleviating symptoms associated with polycystic ovary syndrome. Birth control pills are often prescribed to reverse the effects of excessive androgen levels, and decrease ovarian hormone production.
Hormonal birth control methods such as birth control pills,the contraceptive patch, vaginal ring, contraceptive implant, and hormonal IUD are used to treat cramping and pain associated with primary dysmenorrhea.
Oral contraceptives are prescribed in the treatment of menorrhagia to help regulate menstrual cycles and prevent prolonged menstrual bleeding. The hormonal IUD (Mirena) releases levonorgestrel which thins the uterine lining, preventing excessive bleeding and loss of iron.
Birth control pills are the most commonly prescribed hormonal treatment for hirsutism, as they prevent ovulation and decrease androgen production by the ovaries. Additionally, estrogen in the pills stimulates the liver to produce more of a protein that binds to androgens and reduces their activity.
Modern contraceptives using steroid hormones have perfect-use or method failure rates of less than 1% per year. The lowest failure rates are seen with the implants Jadelle and Implanon, at 0.05% per year. According to Contraceptive Technology, none of these methods has a failure rate greater than 0.3% per year. The SERM ormeloxifene is less effective than the steroid hormone methods; studies have found a perfect-use failure rate near 2% per year.
Long-acting methods such as the implant and the IUS are user-independent methods. For user-independent methods, the typical or actual-use failure rates are the same as the method failure rates. Methods that require regular action by the user—such as taking a pill every day—have typical failure rates higher than perfect-use failure rates. Contraceptive Technology reports a typical failure rate of 3% per year for the injection Depo-Provera, and 8% per year for most other user-dependent hormonal methods. While no large studies have been done, it is hoped that newer methods which require less frequent action (such as the patch) will result in higher user compliance and therefore lower typical failure rates.
Combined vs. progestogen-only
While unpredictable breakthrough bleeding is a possible side effect for all hormonal contraceptives, it is more common with progestogen-only formulations. Most regimens of COCPs, NuvaRing, and the contraceptive patch incorporate a placebo or break week that causes regular withdrawal bleeding. While women using combined injectable contraceptives may experience amenorrhea (lack of periods), they typically have predictable bleeding comparable to that of women using COCPs.
Although high-quality studies are lacking, it is believed that estrogen-containing contraceptives significantly decrease the quantity of milk in breastfeeding women. Progestogen-only contraceptives are not believed to have this effect. In addition, while in general the progestogen-only pill is less effective than other hormonal contraceptives, the added contraceptive effect of breastfeeding makes it highly effective in breastfeeding women.
- There is a mixed effect of combined hormonal contraceptives on the rates of various cancers, with the International Agency for Research on Cancer (IARC) stating: "It was concluded that, if the reported association was causal, the excess risk for breast cancer associated with typical patterns of current use of combined oral contraceptives was very small." and also saying that "there is also conclusive evidence that these agents have a protective effect against cancers of the ovary and endometrium":
- The (IARC) notes that "the weight of the evidence suggests a small increase in the relative risk for breast cancer among current and recent users" which following discontinuation then lessens over a period of 10 years to similar rates as women who never used them, as well as "The increase in risk for breast cancer associated with the use of combined oral contraceptives in younger women could be due to more frequent contacts with doctors" 
- Small increases are also seen in the rates of cervical cancer and hepatocellular (liver) tumours.
- Endometrial and ovarian cancer risks are approximately halved and persists for at least 10 years after cessation of use; although "sequential oral contraceptives which were removed from the consumer market in the 1970s was associated with an increased risk for endometrial cancer".
- Studies have overall not shown effects on the relative risks for colorectal, malignant melanoma or thyroid cancers.
- Information on progesterone-only pills is less extensive, due to smaller sampling sizes, but they do not appear to significantly increase the risk of breast cancer.
- Most other forms of hormonal contraception are too new for meaningful data to be available, although risks and benefits are believed to be similar for methods which use the same hormones; e.g., risks for combined-hormone patches are thought to be roughly equivalent to those for combined-hormone pills.
Combined oral contraceptives can increase the risk of certain types of cardiovascular disease in women with a pre-existing condition or already-heightened risk of cardiovascular disease. Smoking (for women over 35), metabolic conditions like diabetes, obesity and family history of heart disease are all risk factors which may be exacerbated by the use of certain hormonal contraceptives.
There are two main classes of hormonal contraceptives: combined contraceptives contain both an estrogen (usually ethinyl estradiol) and a progestin. Progestogen-only contraceptives contain only progesterone or a synthetic analogue (progestin). Also marketed is ormeloxifene; while not a hormone, ormeloxifene acts on the hormonal system to prevent pregnancy.
The most popular form of hormonal contraception, the combined oral contraceptive pill is known colloquially as the pill. It is taken once a day, most commonly for 21 days followed by a seven-day break, although other regimens are also used. For women not using ongoing hormonal contraception, COCPs may be taken after intercourse as emergency contraception: this is known as the Yuzpe regimen. COCPs are available in a variety of formulations.
The contraceptive patch is applied to the skin and worn continuously. A series of three patches are worn for one week each, and then the user takes a one-week break. NuvaRing is worn inside the vagina. A ring is worn for three weeks. After removal, the user takes a one-week break before inserting a new ring. As with COCPs, other regimens may be used with the contraceptive patch or NuvaRing to provide extended cycle combined hormonal contraception.
A combined injectable contraceptive is a shot given once per month.
The progestogen only pill (POP) is taken once per day within the same three-hour window. Several different formulations of POP are marketed. A low-dose formulation is known as the minipill. Unlike COCPs, progestogen-only pills are taken every day with no breaks or placebos. For women not using ongoing hormonal contraception, progestogen-only pills may be taken after intercourse as emergency contraception. There are a number of dedicated products sold for this purpose.
Hormonal intrauterine contraceptives are known as intrauterine systems (IUS). The only currently available brand is Mirena. An IUS must be inserted by a health professional. Mirena may be used for up to five years. While a copper-containing intrauterine device (IUD) may be used as emergency contraception, the IUS has not been studied for this purpose.
Contraceptive implants are inserted under the skin of the upper arm, and contain progestogen only. Two types of are available; Jadelle (Norplant 2) consists of two rods that release a low dose of hormones. It is effective for five years. Implanon is a single rod that releases a moderate dose of hormones. It is effective for three years.
Ormeloxifene is a selective estrogen receptor modulator (SERM). Marketed as Centchroman, Centron, or Saheli, it is pill that is taken once per week. Ormeloxifene is legally available only in India.
Mechanism of action
The effect of hormonal agents on the reproductive system is complex. It is believed that combined hormonal contraceptives work primarily by preventing ovulation and thickening cervical mucus. Progestogen-only contraceptives can also prevent ovulation, but rely more significantly on the thickening of cervical mucus. Ormeloxifene does not affect ovulation, and its mechanism of action is not well understood.
Combined hormonal contraceptives were developed to prevent ovulation by suppressing the release of gonadotropins. They inhibit follicular development and prevent ovulation as a primary mechanism of action.
Progestogen negative feedback decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the release of follicle-stimulating hormone (FSH) and greatly decreases the release of luteinizing hormone (LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH release prevent a mid-cycle LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation.
Estrogen was originally included in oral contraceptives for better cycle control (to stabilize the endometrium and thereby reduce the incidence of breakthrough bleeding), but was also found to inhibit follicular development and help prevent ovulation. Estrogen negative feedback on the anterior pituitary greatly decreases the release of FSH, which inhibits follicular development and helps prevent ovulation.
Another primary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration through the cervix into the upper genital tract (uterus and fallopian tubes) by decreasing the amount of and increasing the viscosity of the cervical mucus.
The estrogen and progestogen in combined hormonal contraceptives have other effects on the reproductive system, but these have not been shown to contribute to their contraceptive efficacy:
- Slowing tubal motility and ova transport, which may interfere with fertilization.
- Endometrial atrophy and alteration of metalloproteinase content, which may impede sperm motility and viability, or theoretically inhibit implantation.
- Endometrial edema, which may affect implantation.
Insufficient evidence exists on whether changes in the endometrium could actually prevent implantation. The primary mechanisms of action are so effective that the possibility of fertilization during combined hormonal contraceptive use is very small. Since pregnancy occurs despite endometrial changes when the primary mechanisms of action fail, endometrial changes are unlikely to play a significant role, if any, in the observed effectiveness of combined hormonal contraceptives.
Low dose progestogen-only contraceptives include traditional progestogen-only pills, the subdermal implant Jadelle and the intrauterine system Mirena. These contraceptives inconsistently inhibit ovulation in ~50% of cycles and rely mainly on their progestogenic effect of thickening the cervical mucus and thereby reducing sperm viability and penetration.
Intermediate dose progestogen-only contraceptives, such as the progestogen-only pill Cerazette (or the subdermal implant Implanon), allow some follicular development but much more consistently inhibit ovulation in 97–99% of cycles. The same cervical mucus changes occur as with low dose progestogens.
High dose progestogen-only contraceptives, such as the injectables Depo-Provera and Noristerat, completely inhibit follicular development and ovulation. The same cervical mucus changes occur as with very low dose and intermediate dose progestogens.
In anovulatory cycles using progestogen-only contraceptives, the endometrium is thin and atrophic. If the endometrium was also thin and atrophic during an ovulatory cycle, this could theoretically interfere with implantation of a blastocyst (embryo).
Ormeloxifene does not affect ovulation. It has been shown to increase the rate of blastocyst development and to increase the speed at which the blastocyst is moved from the fallopian tubes into the uterus. Ormeloxifene also suppresses proliferation and decidualization of the endometrium (the transformation of the endometrium in preparation for possible implantation of an embryo). While they are believed to prevent implantation rather than fertilization, exactly how these effects operate to prevent pregnancy is not understood.
Frequency of use
Pills—combined and progestogen-only—are the most common form of hormonal contraception. Worldwide, they account for 12% of contraceptive use. 21% of users of reversible contraceptives choose COCPs or POPs. Pills are especially popular in more developed countries, where they account for 25% of contraceptive use.
Injectable hormonal contraceptives are also used by a significant portion—about 6%—of the world's contraceptive users. Other hormonal contraceptives are less common, accounting for less than 1% of contraceptive use.
In 1921, Ludwig Haberlandt demonstrated a temporary hormonal contraception in a female rabbit by transplanting ovaries from a second, pregnant, animal. By the 1930s, scientists had isolated and determined the structure of the steroid hormones and found that high doses of androgens, oestrogens or progesterone inhibited ovulation. A number of economic, technological, and social obstacles had to be overcome before the development of the first hormonal contraceptive, the combined oral contraceptive pill (COCP). In 1957 Enovid, the first COCP, was approved in the United States for the treatment of menstrual disorders. In 1960, the U.S. Food and Drug Administration approved an application that allowed Enovid to be marketed as a contraceptive.
The first progestogen-only contraceptive was introduced in 1969: Depo-Provera, a high-dose progestin injection. Over the next decade and a half, other types of progestogen-only contraceptive were developed: a low-dose progestogen only pill (1973); Progestasert, the first hormonal intrauterine device (1976); and Norplant, the first contraceptive implant (1983).
Combined contraceptives have also been made available in a variety of forms. In the 1960s a few combined injectable contraceptives were introduced, notably Injectable Number 1 in China and Deladroxate in Latin America. A third combined injection, Cyclo-Provera, was reformulated in the 1980s by lowering the dose and renamed Cyclofem (also called Lunelle). Cyclofem and Mesigyna, another formulation developed in the 1980s, were approved by the World Health Organization in 1993. NuvaRing, a contraceptive vaginal ring, was first marketed in 2002. 2002 also saw the launch of Ortho Evra, the first contraceptive patch.
- Susan Scott Ricci, Terri Kyle (2009). "Common Reproductive Issues". Contraception. Lippincott Williams & Wilkins. p. 119.
- Jones, Rachel K. (2011). "Beyond Birth Control: The Overlooked Benefits Of Oral Contraceptive Pills" (PDF). Guttmacher Institute. November.
- National Prescribing Service (11 December 2009). "NPS News 54: Hormonal contraceptives - tailoring for the individual". Retrieved 19 March 2009.
- "Hormonal Contraceptives Offer Benefits Beyond Pregnancy Prevention". The American College of Obstetricians and Gynecologists. Retrieved 5 May 2013.
- "Hirsutism and Polycystic Ovary Syndrome" (PDF). American Society for Reproductive Medicine. Retrieved 5 May 2013.
- "Noncontraceptive Benefits of Birth Control Pills". Reproductivefacts.org. The American Society for Reproductive Medicine. Retrieved 5 May 2013.
- "Dysmenorrhea" (PDF). The American College of Obstetricians and Gynecologists. Retrieved 5 May 2013.
- "Menorrhagia (Heavy Menstrual Bleeding)". The Mayo Clinic. Retrieved 5 May 2013.
- "Hirsutism and Polycystic Ovary Syndrome (PCOS)" (PDF). American Society for Reproductive Medicine. Retrieved 5 May 2013.
- Sivin I, Campodonico I, Kiriwat O, Holma P, Diaz S, Wan L, Biswas A, Viegas O, el din Abdalla K, Anant MP, Pavez M, Stern J (1998). "The performance of levonorgestrel rod and Norplant contraceptive implants: a 5 year randomized study". Hum. Reprod. 13 (12): 3371–8. doi:10.1093/humrep/13.12.3371. PMID 9886517.
- Trussell, James (2007). "Contraceptive Efficacy". In Hatcher, Robert A. et al. Contraceptive Technology (19th rev. ed.). New York: Ardent Media. ISBN 0-9664902-0-7.
- Puri V et al. (1988). "Results of multicentric trial of Centchroman". In Dhwan B. N., et al. (eds.). Pharmacology for Health in Asia : Proceedings of Asian Congress of Pharmacology, 15–19 January 1985, New Delhi, India. Ahmedabad: Allied Publishers.
- Nityanand S et al. (1990). "Clinical evaluation of Centchroman: a new oral contraceptive". In Puri, Chander P.; Van Look, Paul F. A. (eds.). Hormone Antagonists for Fertility Regulation. Bombay: Indian Society for the Study of Reproduction and Fertility.
- O'Connor, M.L. (March–April 2001). "Contraceptive Use Elevates The Odds of Barrier Method Use for Disease Prevention". Family Planning Perspectives (Guttmacher Institute) 33 (2). Retrieved 2009-08-30.
- Paladine, Heather (2003). "What’s New In Contraception". The Female Patient. Retrieved 2009-08-30.
- POP:Kovacs G (October 1996). "Progestogen-only pills and bleeding disturbances". Human Reproduction 11 (Supplement 2): 20–3. doi:10.1093/humrep/11.suppl_2.20. PMID 8982741.
IUS:McCarthy L (2006). "Levonorgestrel-Releasing Intrauterine System (Mirena) for Contraception". Am Fam Physician 73 (10): 1799–. Retrieved 2009-09-01.
Depo-Provera and Jadelle:Hubacher D, Lopez L, Steiner MJ, Dorflinger L (August 2009). "Menstrual pattern changes from levonorgestrel subdermal implants and DMPA: systematic review and evidence-based comparisons". Contraception 80 (2): 113–8. doi:10.1016/j.contraception.2009.02.008. PMID 19631785.
Implanon:Riney S, O'Shea B, Forde A (January 2009). "Etonogestrel implant as a contraceptive choice; patient acceptability and adverse effect profile in a general practice setting". Irish Medical Journal 102 (1): 24–5. PMID 19284015.
- Garceau RJ, Wajszczuk CJ, Kaunitz AM (December 2000). "Bleeding patterns of women using Lunelle monthly contraceptive injections (medroxyprogesterone acetate and estradiol cypionate injectable suspension) compared with those of women using Ortho-Novum 7/7/7 (norethindrone/ethinyl estradiol triphasic) or other oral contraceptives". Contraception 62 (6): 289–95. doi:10.1016/S0010-7824(00)00183-9. PMID 11239615.
- Truitt ST, Fraser AB, Grimes DA, Gallo MF, Schulz KF (October 2003). "Hormonal contraception during lactation: systematic review of randomized controlled trials". Contraception 68 (4): 233–8. doi:10.1016/S0010-7824(03)00133-1. PMID 14572885.
- Kelsey JJ (December 1996). "Hormonal contraception and lactation". Journal of Human Lactation 12 (4): 315–8. doi:10.1177/089033449601200419. PMID 9025449.
- "Maximizing the use of the progestin minipill". Contraceptive Technology Update 20 (2): 19–21. February 1999. PMID 12294591.
- "Progestin-only Contraceptives". Hall Health Primary Care Center. University of Wisconsin-Seattle. 2007-02-11. Retrieved 2009-09-01.
- International Agency for Research on Cancer (IARC) (1999). "5. Summary of Data Reported and Evaluation". Oral Contraceptives, Combined (Vol. 72 ed.). p. 49.
- "Combined Estrogen-Progestogen Contraceptives" (PDF). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans (International Agency for Research on Cancer) 91. 2007.
- IARC Working Group on the Evaluation of Carcinogenic Risks to Humans (1999). "Hormonal contraceptives, progestogens only". Hormonal contraception and post-menopausal hormonal therapy; IARC monographs on the evaluation of carcinogenic risks to humans, Volume 72. Lyon: IARC Press. pp. 339–397. ISBN 92-832-1272-X.
- "McKinley Health Center, University of Illinois: OrthoEvra Contraceptive Patch". Retrieved 2007-07-13.
- Stacey, Dawn (2009-07-28). "Noristerat Injection". About.com. Retrieved 2009-08-29.
- "Centchroman". Reproductive Health Online. 2003. Retrieved 2009-08-29.
- Nelson, Anita L.; Cwiak, Carrie (2011). "Combined oral contraceptives (COCs)". In Hatcher, Robert A.; Trussell, James; Nelson, Anita L.; Cates, Willard Jr.; Kowal, Deborah; Policar, Michael S. (eds.). Contraceptive technology (20th revised ed.). New York: Ardent Media. pp. 249–341. ISBN 978-1-59708-004-0. ISSN 0091-9721. OCLC 781956734. pp. 257–258:
Mechanism of action
COCs prevent fertilization and, therefore, qualify as contraceptives. There is no significant evidence that they work after fertilization. The progestins in all COCs provide most of the contraceptive effect by suppressing ovulation and thickening cervical mucus, although the estrogens also make a small contribution to ovulation suppression. Cycle control is enhanced by the estrogen.
Because COCs so effectively suppress ovulation and block ascent of sperm into the upper genital tract, the potential impact on endometrial receptivity to implantation is almost academic. When the two primary mechanisms fail, the fact that pregnancy occurs despite the endometrial changes demonstrates that those endometrial changes do not significantly contribute to the pill's mechanism of action.
- Speroff, Leon; Darney, Philip D. (2011). "Oral contraception". A clinical guide for contraception (5th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 19–152. ISBN 978-1-60831-610-6.
- Levin, Ellis R.; Hammes, Stephen R. (2011). "Estrogens and progestins". In Brunton, Laurence L.; Chabner, Bruce A.; Knollmann, Björn C. Goodman & Gilman's pharmacological basis of therapeutics (12th ed.). New York: McGraw-Hill Medical. pp. 1163–1194. ISBN 978-0-07-162442-8.
- Glasier, Anna (2010). "Contraception". In Jameson, J. Larry; De Groot, Leslie J. Endocrinology (6th ed.). Philadelphia: Saunders Elsevier. pp. 2417–2427. ISBN 978-1-4160-5583-9.
- "Family Planning Worldwide: 2008 Data Sheet" (PDF). Population Reference Bureau. 2008. Retrieved 2008-06-27. Data from surveys 1997–2007.
- Chandra, A; Martinez GM; Mosher WD; Abma JC; Jones J. (2005). "Fertility, Family Planning, and Reproductive Health of U.S. Women: Data From the 2002 National Survey of Family Growth" (PDF). Vital and Health Statistics (National Center for Health Statistics) 23 (25). Retrieved 2007-05-20. See Table 60.
- Müller-Jahncke WD (Aug 1988). "Ludwig Haberlandt (1885-1932) and the development of hormonal contraception". Z Gesamte Inn Med (in German) (GERMANY, EAST) 43 (15): 420–2. ISSN 0044-2542. PMID 3051743.
- Goldzieher JW (1982). "Estrogens in oral contraceptives: historical perspective". Johns Hopkins Med J 150 (5): 165–9. PMID 7043034.
- Perone N (1993). "The history of steroidal contraceptive development: the progestins". Perspect Biol Med 36 (3): 347–62. PMID 8506121.
- Junod SW, Marks L (2002). "Women's trials: the approval of the first oral contraceptive pill in the United States and Great Britain" (PDF). J Hist Med Allied Sci 57 (2): 117–60. doi:10.1093/jhmas/57.2.117. PMID 11995593.
- Leary, Warren E. (1992-10-30). "U.S. Approves Injectable Drug As Birth Control". The New York Times. p. A.1. PMID 11646958.
- McFadden, Suzanne (2009-06-15). "Golden anniversary of a revolution". The New Zealand Herald. Retrieved 2009-08-29.
- "IUDs—An Update". Population Information Program, the Johns Hopkins School of Public Health. XXIII (5). December 1995.
- Chin, Mona (1992). "The Chronological Important Events in the Development of Norplant". Norplant. Retrieved 2009-08-29., possibly taken from
- Dorflinger, LJ (1991-08-02). "Explanation of assumptions made for Norplant projections". Unpublished. Retrieved 2009-08-29.
- "Research and regulatory approval (of injectable contraceptives)". Population Reports (AccessMyLibrary). 1995-08-01. Retrieved 2009-08-29.
- "World Health Agency Endorsing 2 New Injectable Contraceptives". The New York Times. 1993-06-06. p. Section 1, p.20. Retrieved 2009-08-29.
- Organon (July 16, 2002). "NuvaRing world's first vaginal birth control ring, first launch now in the US" (PDF). Retrieved 2009-08-29.[dead link]
- Associated Press (2001-11-11). "FDA Approves Contraceptive Patch". Wired.com. Retrieved 2009-08-29.
- Singh MM (July 2001). "Centchroman, a selective estrogen receptor modulator, as a contraceptive and for the management of hormone-related clinical disorders". Medical Research Reviews 21 (4): 302–47. doi:10.1002/med.1011. PMID 11410933.