A multinational case-control study of cardiovascular disease and steroid hormone contraceptives: Description and validation of methods

doi:10.1016/0895-4356(95)00516-1

Journal of Clinical Epidemiology

Volume 48, Issue 12, December 1995, Pages 1513-1547

https://doi.org/10.1016/0895-4356(95)00516-1 Get rights and content

Abstract

A hospital-based, case-control study of the association between current usage of oral contraceptives and first-time cases of acute myocardial infarction, stroke, or a venous thromboembolic event (deep vein thrombosis or pulmonary embolus) was carried out in 17 countries from four regions (Africa, Asia, Europe, and Latin America). A total of 3792 cases and 10,281 hospitalised controls matched for age were recruited during a 4-year period, ending in June 1993. The study was designed to have sufficient power to detect a relative risk of 2 for developing each of the three study diseases, associated with current oral contraceptive use in each of the four regions, with the exception of acute myocardial infarction (for which all non-European regions were to be combined) and for venous thromboembolic events in Asia, where these disorders are rare.

This report describes the background, pilot study, methods, and the analyses carried out to validate the methods used in the study.

References (23)

JP Realini et al.
Oral contraceptives and cardiovascular disease: a critique of the epidemiologic studies
Am J Obstet Gynecol
(1985)
DB Thomas
The WHO collaborative study of neoplasia and steroid contraceptives: the influence of combined oral contraceptives on risk of neoplasms in developing and developed countries
Contraception
(1991)
R Russel-Brifel et al.
Prevalence and trends in oral contraceptive use in premenopausal females ages 12–54 years, USA, 1971–1980
Am J Public Health
(1985)
MB Weinberger
Recent trends in contraceptive behaviour
IH Shah
The advance of the contraceptive revolution
World Health Stat Q
(1994)
Jordan WM. Pulmonary embolism. Lancet 2: 1146–1147...
MP Vessey
Female hormones and vascular disease: an epidemiological overview
Br J Fam Planning
(1980)
BV Stadel
Oral contraceptives and cardiovascular disease, part 1
New Engl J Med
(1981)
BV Stadel
Oral contraceptives and cardiovascular disease, part 2
New Engl J Med
(1981)
WF Pratt et al.
Understanding US fertility: findings from the National Survey of Family Growth, Cycle III
Popul Bull
(1984)

M Thorogood et al.

Trends in use of oral contraceptives in Britain

Br J Fam Planning

(1990)

Cited by (73)

Progestin-only contraception and thromboembolism: A systematic review
2016, Contraception
Women with medical conditions associated with increased risk for thrombosis generally should not use estrogen-containing contraceptives; however, less is known about progestin-only contraceptives (POCs) and thrombosis risk.
The objective was to identify evidence regarding the risk of venous thromboembolism (VTE) or arterial thromboembolism [stroke or acute myocardial infarction (AMI)] among women using POCs.
We searched the PubMed database for all articles published from database inception through January 2016 for studies examining thrombosis among women using POCs. We included studies which examined women with medical conditions associated with thrombosis risk, as well as studies of women in the general population (either without these conditions or who were not specified to have these conditions). Hormonal contraceptives of interest included progestin-only pills (POPs), injectables, implants and levonorgestrel-releasing intrauterine devices (LNG-IUDs). Outcomes of interest included VTE, stroke and AMI.
There were 26 articles of good to poor quality that met inclusion criteria; 9 studies examined women with medical conditions and 20 examined women in the general population. Two studies found that, among smokers and women with certain thrombogenic mutations, use of depot medroxyprogesterone acetate (DMPA) had elevated odds of VTE compared with nonsmokers or those without mutations, although confidence intervals were wide and overlapped with odds among nonusers. One study found that, among women with previous VTE, use of POCs (including DMPA) was associated with a nonsignificant increased odds of recurrent VTE (all of which were among DMPA users); two other studies that examined POCs other than DMPA did not observe an association with recurrent VTE. Two studies found that use of DMPA among healthy women was also associated with increased odds of VTE. Two studies found that use of POCs for therapeutic indications was associated with increased odds of VTE. Studies did not find increased odds of VTE with POPs for contraceptive purposes, implants or LNG-IUDs nor were there increased odds of stroke or AMI with any POCs.
The majority of evidence identified by this systematic review did not suggest an increase in odds for venous or arterial events with use of most POCs. Limited evidence suggested increased odds of VTE with use of injectables (three studies) and use of POCs for therapeutic indications (two studies, one with POCs unspecified and the other with POPs). Any increase in risk likely translates to a small increase in absolute numbers of thrombotic events at the population level.
Current issues and available options in combined hormonal contraception
2011, Contraception
Citation Excerpt :
The estrogen-associated increase in VTE appears to be proportional to degree of estrogen exposure and varies with the type of progestin used [55,56]. Surprisingly, third-generation progestins (DSG and GES), which are perceived as safer than other progestins, have been shown to have a twofold (range, 1.6–2.6) higher risk of idiopathic VTE compared with second-generation progestins (LNG and norethindrone) [54,84,85]. These results, however, have been questioned due to methodological bias and confounders in these studies, as other epidemiological studies did not find such a difference [84].
Development of hormonal contraception marked a revolutionary step in social change that has improved the lives of women and families worldwide. Since the first oral contraceptive was introduced in the 1960s, hormonal contraception has undergone various stages of advancement. Today, oral contraceptive regimens are safer and more tolerable, with equal or improved efficacy, than the early formulations. Incremental decreases in the dose of estrogens have helped to alleviate some of the unwanted estrogenic side effects of combined hormonal contraceptives. Progestogens have also evolved over time, and newer generations of progestins have minimal side effects. New delivery methods have further extended the range of options available to women. Among these, the transdermal patch and vaginal ring are widely used. This review examines available combined hormonal contraceptive options and compares them, where data are available, for efficacy, safety, cycle control, adverse events profiles and associated risks, and user preference and satisfaction. We also examine particular areas of interest, including bone mineral density, venous thrombosis and use of antiepileptic drugs.
The Transnational study of oral contraceptive cardiovascular safety: history and science
2009, Journal of Clinical Epidemiology
Citation Excerpt :
The Saskatchewan study was rejected because gestodene was not available in Saskatchewan, and other low-dose COCs, by themselves, were not relevant to the sponsors [6]. Initially called the Trinational study, because it was first conducted in Germany, the United Kingdom and France, it was decided that the study would benefit from emulating as closely as possible the methodology of the study conducted by the World Health Organisation (WHO)'s Human Reproduction Unit [7]. That study, international in nature, was already underway, and its emulation would facilitate comparisons and would allow an eventual combination of data.
Update on the progestin-only contraception
2009, Revue Sage - Femme
Bien qu’elle demeure relativement mal cernée, l’utilisation des progestatifs au sein des différentes contraceptions augmente régulièrement en France (particulièrement le dispositif intra-utérin, l’implant sous-cutané et les microprogestatifs). Sa prescription se fait dans un certain nombre de cas hors des indications d’autorisation de mise sur le marché (particulièrement pour les macroprogestatifs) et elle regroupe une grande variété de molécules, voies d’administration et posologies. Pour ces raisons, un comité d’experts a été réuni et a répondu aux 35 questions posées par un comité d’organisation. Le choix de ces questions était largement inspiré des points litigieux ou peu consensuels rencontrés en pratique clinique courante lors de la prescription d’une contraception progestative. Les réponses apportées ont été largement basées sur les données issues de la littérature médicale. Dans les cas où l’absence d’étude ne permettait pas de répondre de façon formelle à la question posée, le comité d’experts a proposé la réponse la plus consensuelle possible. L’ensemble des réponses apportées par le comité d’experts a ensuite été soumis à un comité d’évaluation avant validation finale du document. La contraception progestative présente différents niveaux d’action (local et/ou central), variables d’une molécule à l’autre. Elle bénéficie d’une efficacité satisfaisante (celle des macroprogestatifs n’a jamais été évaluée) mais suppose le respect de schéma posologique strict (en particulier pour la contraception microprogestative). Il n’a jamais été mis en évidence d’augmentation significative du risque de cancer du sein par l’utilisation de contraception progestative. Cependant, pour plusieurs raisons, l’interprétation des études portant sur le sujet doit rester prudente. Si les effets souvent mal connus des différents progestatifs sur la densité minérale osseuse semblent pouvoir varier selon les molécules, en particulier en raison du taux d’estradiol plasmatique qu’elles induisent, il n’existe pas d’argument direct pour considérer la contraception progestative comme facteur de risque de fracture osseuse. Concernant le risque de maladie thromboembolique veineuse, les progestatifs seuls ne sont pas considérés comme un facteur de risque. La contraception progestative est recommandée : lors d’une mauvaise tolérance des estrogènes exogènes ; pour contrebalancer une hyperestrogénie endogène ; en cas de contre-indication métabolique ou cardiovasculaire aux estroprogestatifs ; en cas de fluctuations hormonales à l’origine de dysphories prémenstruelles ou de migraines cataméniales. Enfin, la contraception progestative constitue une contraception de choix dans certaines situations particulières (allaitement, adénomyose…).
Despite the lack of complete data concerning their effects, the use of progestin-only contraception is increasing in France (particularly the intra-uterine device, the subdermal implantation, and microprogestins). These prescriptions include a broad range of molecules and administration of doses. In some cases, prescriptions of progestogens are made out of the marketing authorisation indications (especially for macroprogestins). For all of these reasons, an Expert Advisory Board has been set up in order to answer the 35 questions addressed by an Expert Organization Board. The choice of these questions was based on controversial or nonconsensual points usually encountered in everyday clinical practice. When possible, answers given were strongly supported by data issued from medical literature. In situations where clinical studies were lacking, the Expert Advisory Board answered in the most consensual way. All answers given by the Expert Advisory Board were subsequently submitted to the Expert Assessment Board before the latest validation of this document. The progestogen only contraception has different levels of action (local and/or central) which may vary from one drug to another. Its prescription is granted satisfactory efficacy (the macroprogestins’ efficacy has never been evaluated) but requires a strict pill-taking routine (especially for the microprogestin contraception). It has never been demonstrated that the use of progestogen is associated with an increased risk of breast cancer. Nevertheless, analysis of breast cancer and progestogen studies should be carried out carefully. Even though the effects, often misunderstood, of the different progestogens on mineral bone density are likely to vary according to the molecules, in particular due to the plasma estradiol level, there is no direct argument for considering the progestin only contraception as a fracture risk factor. As for the venous thromboembolism risk, progestogens are not considered to be risk factors. The progestogen only contraception is advised in the following cases: bad tolerance of exogenous oestrogens; in order to counteract an endogenous hyperoestrogenosis; metabolic or cardiovascular contraindications to estroprogestin; hormonal fluctuations generating premenstrual dysphoria or catamenial headaches. Lastly, the progestin-only contraception should be used as a prime contraception in some particular situations (breast feeding, adenomyosis…).
Update on the progestin-only contraception
2008, Journal de Gynecologie Obstetrique et Biologie de la Reproduction
Bien qu’elle demeure relativement mal cernée, l’utilisation des progestatifs au sein des différentes contraceptions augmente régulièrement en France (particulièrement le dispositif intra-utérin, l’implant sous-cutané et les microprogestatifs). Sa prescription se fait dans un certain nombre de cas hors des indications d’autorisation de mise sur le marché (particulièrement pour les macroprogestatifs) et elle regroupe une grande variété de molécules, voies d’administration et posologies. Pour ces raisons, un comité d’experts a été réuni et a répondu aux 35 questions posées par un comité d’organisation. Le choix de ces questions était largement inspiré des points litigieux ou peu consensuels rencontrés en pratique clinique courante lors de la prescription d’une contraception progestative. Les réponses apportées ont été largement basées sur les données issues de la littérature médicale. Dans les cas où l’absence d’étude ne permettait pas de répondre de façon formelle à la question posée, le comité d’experts a proposé la réponse la plus consensuelle possible. L’ensemble des réponses apportées par le comité d’experts a ensuite été soumis à un comité d’évaluation avant validation finale du document. La contraception progestative présente différents niveaux d’action (local et/ou central), variables d’une molécule à l’autre. Elle bénéficie d’une efficacité satisfaisante (celle des macroprogestatifs n’a jamais été évaluée) mais suppose le respect de schéma posologique strict (en particulier pour la contraception microprogestative). Il n’a jamais été mis en évidence d’augmentation significative du risque de cancer du sein par l’utilisation de contraception progestative. Cependant, pour plusieurs raisons, l’interprétation des études portant sur le sujet doit rester prudente. Si les effets souvent mal connus des différents progestatifs sur la densité minérale osseuse semblent pouvoir varier selon les molécules, en particulier en raison du taux d’estradiol plasmatique qu’elles induisent, il n’existe pas d’argument direct pour considérer la contraception progestative comme facteur de risque de fracture osseuse. Concernant le risque de maladie thromboembolique veineuse, les progestatifs seuls ne sont pas considérés comme un facteur de risque. La contraception progestative est recommandée : lors d’une mauvaise tolérance des estrogènes exogènes ; pour contrebalancer une hyperestrogénie endogène ; en cas de contre-indication métabolique ou cardiovasculaire aux estroprogestatifs ; en cas de fluctuations hormonales à l’origine de dysphories prémenstruelles ou de migraines cataméniales. Enfin, la contraception progestative constitue une contraception de choix dans certaines situations particulières (allaitement, adénomyose…).
Despite the lack of complete data concerning their effects, the use of progestin-only contraception is increasing in France (particularly the intra-uterine device, the subdermal implantation, and microprogestins). These prescriptions include a broad range of molecules and administration of doses. In some cases, prescriptions of progestogens are made out of the marketing authorisation indications (especially for macroprogestins). For all of these reasons, an Expert Advisory Board has been set up in order to answer the 35 questions addressed by an Expert Organization Board. The choice of these questions was based on controversial or nonconsensual points usually encountered in everyday clinical practice. When possible, answers given were strongly supported by data issued from medical literature. In situations where clinical studies were lacking, the Expert Advisory Board answered in the most consensual way. All answers given by the Expert Advisory Board were subsequently submitted to the Expert Assessment Board before the latest validation of this document. The progestogen only contraception has different levels of action (local and/or central) which may vary from one drug to another. Its prescription is granted satisfactory efficacy (the macroprogestins’ efficacy has never been evaluated) but requires a strict pill-taking routine (especially for the microprogestin contraception). It has never been demonstrated that the use of progestogen is associated with an increased risk of breast cancer. Nevertheless, analysis of breast cancer and progestogen studies should be carried out carefully. Even though the effects, often misunderstood, of the different progestogens on mineral bone density are likely to vary according to the molecules, in particular due to the plasma estradiol level, there is no direct argument for considering the progestin only contraception as a fracture risk factor. As for the venous thromboembolism risk, progestogens are not considered to be risk factors. The progestogen only contraception is advised in the following cases: bad tolerance of exogenous oestrogens; in order to counteract an endogenous hyperoestrogenosis; metabolic or cardiovascular contraindications to estroprogestin; hormonal fluctuations generating premenstrual dysphoria or catamenial headaches. Lastly, the progestin-only contraception should be used as a prime contraception in some particular situations (breast feeding, adenomyosis…).
Central Venous Sinus Thrombosis in a Young Woman Taking Norethindrone Acetate for Dysfunctional Uterine Bleeding: Case Report and Review of Literature
2008, Journal of Obstetrics and Gynaecology Canada
The association between the progestin-only pill used for treatment of menstrual disorders and central venous sinus thrombosis (CVST) has rarely been reported in the literature. This report describes a case of central venous sinus thrombosis following intake of norethindrone acetate for dysfunctional uterine bleeding secondary to polycystic ovary syndrome in a young woman with undiagnosed underlying hyperhomocysteinemia.
A 23-year-old woman presented with severe headache, followed by hemiparesis, seizures, and altered sensorium. She had been prescribed norethindrone acetate for the management of dysfunctional uterine bleeding secondary to polycystic ovary syndrome. Investigations revealed acquired hyperhomocysteinemia, presumably due to nutritional deficiencies, and evidence of CVST on MRI and magnetic resonance venography. Investigations showed no evidence of inherited thrombophilia. The patient was treated with low molecular weight heparin, followed by warfarin, vitamin B₁₂, vitamin B₆, and folic acid, and recovered successfully.
Although venous thrombosis is usually linked to the ingestion of estrogen, rather than progestogen, this case illustrates that patients who are prescribed progestogen-only pills for gynaecological disorders may develop thrombosis, especially if they have predisposing metabolic disorders.
L’association entre la thrombose du sinus veineux central (TSVC) et l’utilisation de la pilule ne faisant appel qu’à un progestatif pour la prise en charge des troubles menstruels a rarement fait l’objet d’articles au sein de la littérature. Ce rapport décrit un cas de thrombose du sinus veineux central survenu à la suite de l’administration d’acétate de noréthindrone pour la prise en charge de saignements utérins dysfonctionnels attribuables au syndrome des ovaires polykystiques, chez une jeune femme présentant une hyperhomocystéinémie sous-jacente non diagnostiquée.
Une femme de 23 ans présentait de graves maux de tête, suivis d’une hémiparésie, de convulsions et d’une altération du sensorium. On lui a prescrit de l’acétate de noréthindrone pour la prise en charge de saignements utérins dysfonctionnels attribuables au syndrome des ovaires polykystiques. Les explorations ont révélé la présence d’une hyperhomocystéinémie acquise (vraisemblablement en raison de carences nutritionnelles) et de signes de TSVC (révélés par IRM et veinographie par résonance magnétique). Elles n’ont révélé aucun signe de thrombophilie héréditaire. La patiente a été traitée au moyen d’héparine de faible masse moléculaire, suivie de warfarine, de vitamine B₁₂, de vitamine B₆ et d’acide folique; elle a récupéré avec succès.
Bien que la thrombose veineuse soit habituellement liée à l’ingestion d’œstrogènes, plutôt qu’à celle d’un progestatif, ce cas illustre que les patientes à qui l’on prescrit des pilules ne faisant appel qu’à un progestatif pour contrer des troubles gynécologiques peuvent en venir à présenter une thrombose, particulièrement en présence de troubles métaboliques prédisposants.

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^∗: Funded by: UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction and the National Institutes of Health Contraceptive and Reproductive Evaluation Branch [contract National Institutes of Child Health and Human Development (NICHD) NO1-HD-0-2914].

^†: Centres and principal investigators: Myriam Debert-Ribeiro, Departmento de Medicina Preventiva, Escola Paulista de Medicina, Sao Paulo, Brazil; Ernesto Medina, Escuela de Salud Publica, Universidad de Chile, Santiago, Chile; Jorge Artigas, Departmento de Salud Publica, Escuela de Medicina, Valparaiso, Chile; Shen He, National Research Institute for Family Planning, Beijing, China; Zhong Yu Hui, Sichuan Family Planning Research Institute, Chengdu, China; Zhang De-Wei, Shanghai Institute for Planned Parenthood Research, Shanghai, China; Oscar Rojas, Facultad de Salud, Universidad del Valle, Cali, Colombia; Martin Vessey, Department of Public Health and Primary Care, University of Oxford, Oxford, UK; Lothar Heinemann, Zentrum fur Epidemiologie and Gesundheitsforschung, Berlin, Germany; Stuart Donnan and Suzanne Ho, Department of Community Medicine, Chinese University of Hong Kong, Hong Kong; Gyorgy Bartfai, Department of Obstetrics and Gynaecology, University Medical School, Szeged, Hungary; J. Kisjanto, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia; Rainford Wilks, Tropical Metabolism Research Unit, University of the West Indies, Kingston, Jamaica; Reuben Agwanda, Kenya Medical Research Institute, Nairobi, Kenya; Rossario Ruiz, Grupo Interuniversitario Mexicano de Investigaçion Epidemiologica en Salud Reproductiva, Durango, Mexico; Mateja Kozuh-Novak, University Institute of Public Health, Ljubljana, Slovenia; Nikorn Dusitsin, Pramuan Virutamasen, and Kammant Phanthumchinda, Department of Obstetrics and Gynaecology, Chulalongkorn Hospital, Suporn Koetsawang, Siriraj Family Planning Research Center, Siriraj Hospital, Bangkok, Thailand; Jasenka Demirovic and Karen Belkic, School of Medicine, University of Belgrade, Belgrade, Federal Republic of Yugoslavia; W.S. Mwandila and C.M. Mutale, University Teaching Hospital, Lusaka, Zambia; and Jonathan Matenga and Adrian Wilson, Department of Medicine, University of Zimbabwe, Harare, Zimbabwe.

^§: Study and data coordination: N.R. Poulter (Study Coordinator and Co-Principal Investigator); C.L. Chang (Statistician and Data Manager); S. Lawley (Data Processor); M.G. Marmot (Co-Principal Investigator); S. Smith (Data Processor); Department of Epidemiology and Public Health, University College London Medical School, London, UK.

^∥: Publications advisory committee: T.M.M. Farley, UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland; J. Kelaghan, National Institutes of Health, Bethesda, MD, USA; M.G. Marmot, University College London Medical School, London, UK; O. Meirik, UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland; J. Olsen, Danish Epidemiology Science Centre, University of Aarhus, Denmark; and M. Thorogood, London School of Hygiene and Tropical Medicine, London, UK.

^#: Manuscript prepared by: N.R. Poulter, C.L. Chang, T.M.M. Parley, and M.G. Marmot.

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Special communicationA multinational case-control study of cardiovascular disease and steroid hormone contraceptives: Description and validation of methods

Abstract

Am J Obstet Gynecol

Contraception

Prevalence and trends in oral contraceptive use in premenopausal females ages 12–54 years, USA, 1971–1980

Am J Public Health

Recent trends in contraceptive behaviour

The advance of the contraceptive revolution

World Health Stat Q

Female hormones and vascular disease: an epidemiological overview

Br J Fam Planning

Oral contraceptives and cardiovascular disease, part 1

New Engl J Med

Oral contraceptives and cardiovascular disease, part 2

New Engl J Med

Understanding US fertility: findings from the National Survey of Family Growth, Cycle III

Popul Bull

Trends in use of oral contraceptives in Britain

Br J Fam Planning

Special communication
A multinational case-control study of cardiovascular disease and steroid hormone contraceptives: Description and validation of methods