Abstract
Scientific background
A large proportion of women of reproductive age in Germany use various methods of pregnancy prevention (contraception), among them various hormone-based methods. Hormonal contraceptives may be divided into combined estrogen-progestogen contraceptives (pills, skin patches, vaginal rings), progestogen-only contraceptives (pills, injections, implants, hormone spirals) and emergency contraceptives.
Research questions
The evaluation addressed the question of benefits and risks of hormonal contraceptives, their economic effects as well as their ethical-social and legal implications.
Methods
A systematic literature search was conducted in April 2006 starting from 2000. The evaluation is primarily based on systematic reviews.
Results
In perfect use, all hormonal contraceptives excluding emergency contraceptives proved to be the most effective reversible contraceptive methods (rate of unintended pregnancies 0.05% to 0.3%). However, the typical use of oral contraceptives, injections, skin patches, and vaginal rings, which also considers possible application errors, showed a lower contraceptive efficacy (rate of unintended pregnancies 3% to 8%). It was lower than that of copper spirals.
The risk of venous thromboembolism increased three to six times in users of hormonal contraceptives, the risks of stroke and myocardial infarction two to three times. The risk declined after discontinuation of use. The effects were estrogen-dose and progestogen-type dependent.
The use of hormonal contraceptives showed a relative risk of ovarian and endometrial carcinomas of approximately 0.5 or 0.7, of breast and cervical cancer of approximately 1.2 or 1.6. The effect remained several years after discontinuation of use. The results concerning hepatocellular carcinoma suggested a carcinogenic effect.
In women with acne, an improvement due to use of hormonal contraceptives was proven. Cervical chlamydial infections were more frequent in users of hormonal contraception. Headache appeared mostly only at the beginning of the use of combined oral contraceptives. Progestogen-only contraceptives worsened the results of the glucose tolerance test. A review of low evidence reported further risks of hormonal contraceptives (concerning menstrual problems, ovarian cysts, bone density, thyroid diseases and rheumatoid arthritis) as well as further benefits (concerning blood pressure and Crohn’s disease).
Hormonal spirals were shown to be more effective than spirals which do not release hormones. In emergency contraception, Levonorgestrel was more effective than the Yuzpe method. Most other proven differences between hormonal contraceptives were related to menstrual problems.
After spirals with or without hormone release, the other hormonal contraceptives were shown in typical use to be the second most cost-effective reversible methods of contraception.
Discussion
The addressed questions could be answered only on relatively low evidence level, partly only for applications with estrogen doses which are not used in Germany any more. The transferability of the results of the analysed primary health-economics studies on the current situation in Germany is limited (clinical assumptions from out-dated information sources of low evidence levels, cost assumptions from the American health system).
Conclusions
In perfect use, hormonal contraceptives have to be classified as the most effective reversible contraceptive methods. For the individual decision concerning the use of hormonal contraception, benefits should be related to the additional risks. Alternative methods such as spirals should be prioritised if perfect use seems to be impossible. In this case, spirals are also preferable from health-economics perspective. No ethical-social or legal conclusions can be derived from the available data.
Abstract
Wissenschaftlicher Hintergrund
In Deutschland verwendet ein großer Teil der Frauen im reproduktiven Alter unterschiedliche Maßnahmen zur Schwangerschaftsverhütung (Kontrazeption), darunter verschiedene Methoden mit Einsatz von Hormonen. Hormonale Kontrazeptiva lassen sich in Östrogen-Gestagen-Kombinationspräparate (Tabletten, Pflaster, Vaginalringe), Gestagen-Monopräparate (Tabletten, Spritzen, Implantate, Hormonspiralen) und Notfallkontrazeptiva („Pille danach“) unterteilen.
Forschungsfragen
Die Bewertung untersuchte die Fragen nach medizinischem Nutzen und Risiken hormonaler Kontrazeptiva, ihren gesundheitsökonomischen Effekten sowie ethisch-soziale und juristische Implikationen.
Methodik
Eine systematische Literaturrecherche wurde im April 2006 für den Zeitraum ab 2000 durchgeführt. Die Bewertung basiert primär auf systematischen Literaturübersichten.
Ergebnisse
Bei perfekter Anwendung erwiesen sich alle hormonalen Kontrazeptiva mit Ausnahme der Notfallkontrazeptiva als die wirksamsten reversiblen kontrazeptiven Methoden (Rate ungewollter Schwangerschaften: 0,05% bis 0,3%). Bei typischer Anwendung, die auch mögliche Anwendungsfehler berücksichtigt, zeigten allerdings hormonale orale Kontrazeptiva, Injektionen, Pflaster und Vaginalringe eine niedrigere Wirksamkeit (Rate ungewollter Schwangerschaften: 3% bis 8%). Diese war geringer als bei Kupferspiralen.
Das Risiko für venöse Thromboembolien war bei Anwenderinnen hormonaler Kontrazeptiva drei- bis sechsfach, für Schlaganfälle und Myokardinfarkte zwei- bis dreifach erhöht und ging nach der Medikamentenabsetzung zurück. Das Risiko war von Östrogendosis und Gestagentyp abhängig.
Beim Einsatz hormonaler Kontrazeptiva zeigte sich für Ovarial- und Endometriumkarzinome eine ca. 0,5- bzw. 0,7-fache Risikoreduktion, für Brustkrebs und Zervixkarzinom eine ca. 1,2- bzw. 1,6-fache Risikoerhöhung. Der Effekt blieb einige Jahre nach Medikamentenabsetzung bestehen. Ergebnisse hinsichtlich hepatozellulärer Karzinome sprachen eher für einen kanzerogenen Effekt.
Bei Frauen mit Akne zeigte sich eine Verbesserung durch hormonale Kontrazeptiva. Zervikale Chlamydieninfektionen traten bei den Anwenderinnen häufiger auf, Kopfschmerzen hingegen meistens nur am Anfang der Anwendung kombinierter oraler Kontrazeptiva. Gestagen-Monopräparate verschlechterten die Ergebnisse des Glukosetoleranztests. Nachweise für weitere Nutzen (Menstruationsbeschwerden, Ovarialzysten, Knochendichte, Schilddrüsenerkrankungen, rheumatoide Arthritis) und weitere Risiken (Blutdruckhöhe, Morbus Crohn) stammen aus einer Publikation niedriger Evidenzebene.
Hormonspiralen zeigten sich wirksamer als Spiralen ohne Hormonfreisetzung. Bei Notfallkontrazeption war Levonorgestrel wirksamer als die Yuzpe-Methode. Unterschiede zwischen verschiedenen hormonalen Kontrazeptiva bezogen sich meistens auf den Verlauf des Menstrualzyklus.
Nach Spiralen mit bzw. ohne Hormonfreisetzung erwiesen sich die anderen hormonalen Kontrazeptiva bei typischer Anwendung als die kostenwirksamsten reversiblen kontrazeptiven Methoden.
Diskussion
Die Fragestellungen konnte nur auf relativ niedriger Evidenzbasis beantwortet werden, zum Teil nur für Präparate mit Östrogendosen, die in Deutschland nicht mehr angewendet werden. Die Ergebnisse der ausgewerteten gesundheitsökonomischen Primärstudien sind schlecht auf die aktuelle Situation in Deutschland übertragbar (klinische Annahmen aus veralteten Informationsquellen niedriger Evidenzebenen, Kostenannahmen aus dem amerikanischen Gesundheitssystem).
Schlussfolgerungen
Hormonale Kontrazeptiva sind bei perfekter Anwendung als die wirksamsten reversiblen kontrazeptiven Methoden einzustufen. Bei der individuellen Entscheidung über eine hormonale Kontrazeption sollen Nutzen und Risiken gegenübergestellt werden. Bei Anzeichen, dass perfekte Anwendung nicht möglich sein wird, sollten Verhütungsmethoden in Form von Spiralen oder Hormonimplantaten priorisiert werden. In diesem Fall sind Kontrazeptiva auf Spiralenbasis auch aus gesundheitsökonomischer Sicht zu bevorzugen. Aus den vorhandenen Daten lassen sich keine ethisch-sozialen und juristischen Schlussfolgerungen ableiten.
Executive Summary
1. Scientific background
Background to pregnancy prevention
Conception is defined as the fusion of an egg cell with a sperm cell. Should the fertilised egg nest in the uterus, pregnancy evolves and most often results in birth. Methods which enable sexual intercourse without pregnancy, or with reduced risk of pregnancy, are defined as methods of pregnancy prevention. Currently, nearly 17.2 million women (41% all women) in Germany are of reproductive age. A large proportion of these women use various methods of pregnancy prevention.
The methods for pregnancy prevention may be divided into methods which use hormones and those which do not. Evaluating these methods should differentiate between their perfect and typical use, which also considers possible application errors.
Pregnancy prevention methods which do not use hormones are: methods without the use of any appliances (abstinence and discontinuation of sexual intercourse), chemical contraceptives (spermicides), mechanical contraceptives (condoms, spirals, vaginal rings), surgical contraception (tubal ligation, vasectomy) as well as simultaneous combination of several methods.
Pregnancy prevention methods with the use of hormones may be divided in: combined estrogen-progestogen contraceptives (pills, skin patches, vaginal rings), progestogen-only contraceptives (pills, injections, implants, hormone spirals) and emergency contraceptives.
Pregnancy prevention methods which use hormones
Combined estrogen-progestogen and progestogen-only hormone contraceptives are used for pregnancy prevention. The estrogen compound ethinyl estradiol is applied in most combined contraceptives, in a few others mestranol or estradiol cypionat. The daily dose of estrogens in the first preparations was more than 50 µg/day and declined through further development down to 20 to 30 µg/day in current applications.
In the literature, progestogen compounds in contraceptives are often divided into three generations according to the development period (beginning of the 60s, 70s and 80s). Compounds of the first generation are norethindron, ethynodiol diacetate, lynestrenol, norethynodrel and dienogest, of the second levonorgestrel, norgestrel, and norgestrione, of the third desogestrel, norgestimate and gestodene. Further agents, such as drospirenone, cyproteron acetate and chlormadion acetate, are defined as unclassified.
Cost of hormone contraceptives
The German retail price of N2 packages (for three cycles) of oral contraceptives is approximately 21 to 37 euros, of three-month-injections 29 to 30 euros, of skin patches and of vaginal rings 38 to 40 euros. The price of hormone implants is quoted as 194 euros per three years use, for emergency contraceptives 16 to 18 euros per single use. To compare: the cost for one package of spermicide in Germany is approximately 10 to 5 euros, for one male condom 0.50 euros, for one female condom 5 euros, for a diaphragm 20 euros, for a cervical cap 25 euros, for a copper spiral 150 euros, for a hormone implant 300 euros, and for a hormone spiral 300 euros.
2. Research questions
This report addresses the following questions:
What are the medical benefits and risks of the use of hormone contraceptives for women?
What are the health-economics consequences of the use of hormone contraceptives?
Which ethical implications must be noted?
3. Medical evaluation
3.1 Methods
The literature was searched in April 2006, beginning from 2000 in the most important medical electronic databases (MEDLINE, MEDLINE Alert, EMBASE, EMBASE Alert, SciSearch, BIOSIS, DAHTA-database, Cochrane Database of Systematic Reviews etc.). Further systematic reviews were identified through searches in publications´ reference lists and expert contacts.
The medical analysis is primarily based on systematic reviews concerning benefits and risks of hormone contraceptives.
Besides contraceptive effectiveness, the most prevalent and worst side-effects (thromboses and neoplasies) were primarily considered as clinically relevant endpoints.
The information synthesis was done qualitatively. In conclusion, the results of information synthesis for each parameter were attributed to the following evidence levels according to the reccomendations of the Oxford Centre for Evidence-Based Medicine: evidence from systematic review of randomised controlled trials (1a), clinical controlled studies (2a), case-control-studies (3a) and from non-systematic reviews (4).
3.2 Results
Effectiveness
In perfect use, hormonal contraceptives (except emergency contraceptives) proved to be the most effective reversible contraceptive methods (rate of unintended pregnancies 0.05% to 0.3%). Typical use of hormonal contraceptives in the form of pills, injections, patches, and vaginal rings showed a lower effectiveness (rate of unintended pregnancies 3% to 8%). However, this contraceptive effect was greater than the effects of all reversible hormonal contraceptives with the exception of copper spirals (evidence level 4).
Thrombotic effects
The risk of venous thromboembolism increased three to six times in users of hormonal contraceptives in comparison with non-users and declined within three months of discontinuation of applications. Users of hormonal contraceptives with inherent mutations (especially with factor V-Leiden) had a considerably higher risk of venous thromboembolism. The risk of venous thromboembolism increased with higher estrogen dose. Progestogen-only contraceptives did not demonstrate a significant effect on venous thromboembolism in any study. Contraceptives of the third generation showed a higher risk in comparison with compounds of the second generation (evidence level 2a).
The risks of stroke and myocardial infarction increased two to three times in users of hormonal contraceptives in comparison with non-users and declined after discontinuation of use. This effect was also estrogen-dose dependent. The risk of stroke increased in the contraceptives with progestogens of the first, second and third generations, the risk of myocardial infarction in the applications with progestogens of the first and second generations (evidence level 2a).
Neoplastic effects
For ovarian and endometrial carcinomas, a 0.5 and 0.7 risk reduction was shown by the use of hormonal contraceptives. This benefit increased with longer use of applications and persists 15 to 20 years after medicament discontinuation (evidence level 2a).
Results for breast and cervical cancer showed an approximately 1.2 and 1.6-fold risk increase. The risk of breast cancer was higher in younger women and the risk of cervical cancer with longer duration of the medicament use (evidence level 2a). The increased risk persisted several years after discontinuation (evidence level 2a).
The association between exposure to hormonal contraceptives and the risk of hepatocellular carcinoma as well as of colorectal carcinomas was inconsistent in the studies. It suggested a carcinogenic effect of hormonal contraceptives on hepatocellular carcinoma (evidence level 2a).
Other effects of hormonal contraceptives
In patients with acne, a reduction of the number of lesions as well as their severity, was proven (evidence level 1a).
The studies' results concerning sexually transmitted diseases were heterogenic for most infections and yielded evidence only for an increase of cervical chlamydial infection (evidence level 2a). Headache, if it appeared, came mainly at the beginning of the use of combined oral contraceptives (evidence level 2a). Progestogen-only contraceptives deteriorated the results of the glucose tolerance test (evidence level 2a).
A publication of low evidence reported further risks of hormonal contraceptives concerning menstrual problems, ovarian cysts, low bone density, thyroid diseases, rheumatoid arthritis as well as further benefits with regard to blood pressure and Crohn’s disease (evidence level 4).
Comparison of various hormonal with non-hormonal contraceptives
In the direct comparison of spirals with and without release of hormones, an additional contraceptive effect of hormones was proven (evidence level 1a).
Comparison of various hormonal contraceptives among each other
In emergency contraception, levonorgestrel is more effective in comparison with the Yuzpe method (estrogen-progestogen combination, two times within twelve hours, evidence level 1a). Most other proven effects (except of thrombotic effects, see above) were related to menstrual problems.
3.3 Discussion
For the most endpoints evaluated, the addressed question could be answered only on a relatively low evidence level. In many publications, studies with different estrogen doses and progestogen types were summarised. Therefore, for many endpoints it is unclear whether the currently-used contraceptives in Germany with low estrogen dose and different progestogen types have the same effectiveness.
4. Economic evaluation
4.1 Methods
The literature was searched in April 2006, beginning from 2000 in the most important electronic databases (MEDLINE, MEDLINE Alert, EMBASE, EMBASE Alert, SciSearch, BIOSIS, DAHTA-database, Cochrane Database of Systematic Reviews etc.). Further systematic reviews were identified through searches in publication’s reference lists.
The studies' design, medical and economic assumptions as well as model assumptions, were evaluated in the presented analysis. Additionally, the transferability of the results to the current situation in Germany was checked.
4.2 Results
Two relevant health-economics studies could be included in the analysis.
In typical use, Levonorgestrel and copper spirals were shown to be the most cost-effective reversible methods of contraception. Hormonal contraceptives without spirals were the next cost-effective reversible methods of contraception; the depot-medroxyprogesteron-acetate injections showed better cost-effectiveness than other appliances. Non-hormone-based methods without spirals were less cost-effective. Each method of contraception was shown to be more cost-effective than no use of contraception.
4.3 Discussion
Both studies showed some shortcomings: clinical assumptions were derived from out-dated information sources of low evidence levels and cost assumptions from the American health system for the year 2001 or 2002. Therefore, the transferability of the results to the current situation in Germany is limited.
5. Ethical/social and legal aspects
5.1 Methods
The literature was searched in the most important medical electronic databases. Publications for the ethical-social and legal analysis could be included only if they were primarily concerned with ethical, social or legal aspects in the use of hormonal contraceptives for healthy women of reproductive age.
5.2 Results
The literature search was conducted in April 2006 beginning from 2000 and yielded 173 hits. However, no relevant publications could be included in the analysis. Information about these aspects was used from the German Federal Centre for Health Education.
5.3 Discussion
According to the existing information about ethical and social aspects, the use of modern hormonal contraceptives seems to be relatively unproblematic. No proposal may be derived from the presented report concerning possible changes to the law.
6. Summary discussion of all results
For the most endpoints evaluated, the addressed questions could be answered only on a relatively low evidence level. In many publications, studies with different estrogen doses and progesogen types were summarised. Therefore, for many endpoints it is unclear whether the currently-used contraceptives in Germany with low estrogen dose and various progestogen types have the same effectiveness. The transferability of the results of the analysed primary health-economics studies on the current situation in Germany is only limited (clinical assumptions from out-dated information sources of low-evidence levels, cost assumptions from the American health system). The efficacy assumptions reflect only the typical use of contraceptives.
7. Conclusions
In perfect use, hormonal contraceptives (except emergency contraceptives) must be classified as the most effective reversible methods of the prevention of unintended pregnancies. For a better efficacy of hormonal contraceptives in the form of pills, injections, patches and vaginal rings under everyday conditions, interventions to improve the quality of use should be applied. Alternative methods, such as spirals with or without hormone release or hormone implants, should be prioritised if perfect use seems to be impossible.
For the individual decision concerning the use of hormonal contraceptives an individual patient’s risk of thrombotic events (thromboembolism, stroke, myocardial infarction) should be estimated. Women with inherited mutations (especially with factor V-Leiden) should not use these applications.
The benefit of avoided ovarian and endometrial cancer should be related to additional risks of breast, cervical and hepatocellular carcinoma.
In women with acne, an improvement through the use of hormonal contraceptives may be expected. Cervix chlamydial infections appear to be more frequent in users than in non-users of hormonal contraceptives.
Hormonal contraceptives may cause further benefit with regard to menstrual problems, ovarian cysts, low bone density, thyroid diseases und rheumatoid arthritis as well as further risks with regard to blood pressure and Crohn’s disease.
The best application for all women cannot be derived from the presented report. Most differences between applications were related to menstrual problems.
The decision should be met individually by physicians and women. In general, combined preparations with low estrogen-dose and progestogen-only applications should be preferred. In emergency contraception, the use of levonorgestrel should be prioritised.
From a health-economics perspective in typical use the application of contraceptives on the basis of spirals is to be preferred, corresponding data in perfect use are still missing. No ethical-social or legal conclusions can be derived from the available data.
For a quantitative benefit-risk assessment of currently-used applications, the analysis of primary studies with an exclusive view on these applications is recommended. For an estimate of the incremental cost-effectiveness, a detailed health economic modelling with application of the current prices and costs in Germany would be required.