Is an EMA review on hormonal contraception and thrombosis needed?BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f1464 (Published 07 March 2013) Cite this as: BMJ 2013;346:f1464
All rapid responses
Rosendaal and Helmerhorst would like a European Medicines Agency (EMA) review on hormonal contraceptives and write, “for a drug, effectiveness needs to be proven, harm does not: reasonable doubt about harm is sufficient to render prescribing a drug irresponsible”. Far from reasonable doubt, there is absolute proof that thrombosis is only one of many different types of harm caused by progesterone dominant contraceptives.
Breast cancers, HPV infections and cervical cancers, HIV transmission, and antidepressant use are also increasing with increases in hormone use by younger women.
In the United States, the incidence of metastatic stage IV breast cancer increased by 78% (average increase 2.07% per year) in women aged 25 to 39 from 1976 to 2009 (34 years). For this age group the national 5-year survival was 31% and the 10-year overall survival below 20%.1
In England, cervical cancer increased significantly (APC 2.16) in 20-29-year-olds from1992 to 2006.2 Progesterone contraceptives can cause immunosuppression, increase the risk of HPV, and cervical cancer.3-4
In Africa, use of depot progesterone acetate doubled the risk of HIV transmission from males to females or from females to males.5-6
In Sweden, a million women study found progestin-only takers were significant more likely to use antidepressants with the highest risk in 16-19 year olds using either progestin-only or combined hormonal contraceptives.7
Longer and earlier age maternal hormone use may also have contributed to the dramatic increases in autism, which is said to be the fastest growing developmental disorder in the world today.8,9
In the USA, autism increased from 1 in 2500 in 1970 to 1 in 88 children (1 in 54 boys) in 2008 in a study of 300,000 8-year-old children.8 Relative increases were 200-600% from the 2003 autism estimates to the 2007 ASD estimates. Lifetime individual care costs can be over 3 million US dollars. Autism impacts many systems in the body, including the metabolic, mitochondrial, immunological, gastrointestinal and the neurological systems.9
In the UK, John McLaren-Howard analyses a very extensive range of chemical and metal genomic DNA adducts in leucocytes. He finds toxic DNA adducts in some women taking hormones, some cancer patients and some autistic children. Commonest adducts are malondialdehyde, probably from lipid peroxidation secondary to poor superoxide dismutase activity and copper/zinc upsets; also nickel complex on the hormone receptor enzyme adenylate cyclase gene; nickel which part-blocks the expression of cytoplasmic superoxide dismutase; and, also cadmium and mercury adducts. Preliminary results are summarized at www.harmfromhormones.co.uk.
Evidence of increases in proven, or even possible, serious harm from hormone use should not be overlooked because of the great need for effective contraception.
1 Johnson RH, Chein FL, Bleyer A. Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009. JAMA 2013;309(8):800-805.
2 Foley G, Alston R, Geraci M, Brabin L, Kitchener H, Birch J. Increasing rates of cervical cancer in young women in England: an analysis of national data 1982-2006. Br J Cancer 2011;105:177-84.
3 Brabin L. Interactions of the female hormonal environment, susceptibility to viral infections, and disease progression. AIDS Patient Care STDS 2002;16:211-21.
4 Huijbregts RP, Helton ES, Michel KG, Sabbaj S, Richter HE, Goepfert PA, Hel Z. Hormonal Contraception and HIV-1 Infection: Medroxyprogesterone acetate suppresses innate and adaptive immune mechanisms. Endocrinology 2013;154:282-95.
5 Heffron R, Donnell D, Rees H, et al; Partners in Prevention HSV/HIV Transmission Study Team. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. The Lancet Infectious Diseases, 2012;12:19 – 26.
6 Gollub E, Stein Z. Living with uncertainty: acting in the best interests of women. AIDS Res Treat. 2012;2012:524936.
7 Wiréhn AB, et al. Use of hormonal contraceptives in relation to antidepressant therapy: A nationwide population-based study. Eur J Contracept Reprod Health Care 2010;15:41-7.
8 Schieve LA, et al. ASD estimates. Matern Child Health J. 2012;16 Suppl 1:S151-7.
9 Randolph-Gips M, Srinivasan P. Modeling autism: a systems biology approach. J Clin Bioinforma 2012;2:17.
Competing interests: No competing interests
In their reaction to our commentary, Drs Cotescu and Waddington vent the opinion that there is no reason for an EMA review, or any concern for that matter, since third generation contraceptives, drospirenone-containing contraceptives and cyprotereone-acetate oral contraceptives are all equally safe.
Their main point is that all studies that are retrospective ‘particularly those based on administrative databases’ are fraught with bias. Undoubtedly it is true that any study can be biased, or wrong by chance, but one has to describe what this bias would be, so each point can be individually judged for its merit. Blanket statements about bias are senseless. This is a point we dealt with over 10 years ago, when we dissected all biases that had been brought forward in a paper in the New England Journal of Medicine . None held true. Since then, many more studies have come out, with very different designs, ranging from nested case-control studies in the UK General Practioners’ Research Database (GPRD) , to cohort studies linking national databases in Denmark , to case control studies basd on insurance claims in managed health care plans in the United States , to our own population-based case control studies in The Netherlands [5,6], and all have confirmed over and over again the increased risk of the abovementioned oral contraceptives over those containing levonorgestrel. In addition to epidemiological studies, laboratory studies have led to the development of methods to assess the overall haemostatic balance, by measuring the so-called endogenous thrombin potential or acquired APC-resistance, which predicts the risk of thrombosis in women and men [7,8]. Application of this test has not only consistently and repeatedly shown a tilt towards a prothrombotic state in healthy users of those oral contraceptives associated with a risk of thrombosis, but also enabled us to warn about a thrombotic risk of drospirenone-containing oral contraceptives even before the body count of epidemiological studies [9,10], a method adopted by the EMA (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidelin...
The main watershed between studies showing a higher risk for those oral contraceptives and those not showing it, is that the latter were invariably paid for or conducted by the manufacturers of those contraceptives. Even the same database (the GPRD) showed an increased risk of 3rd generation oral contraceptives when analysed with public funding , and the absence of any risk when bought by one of the manufacturers and then re-analysed . This is empirical evidence for what we wrote in a commentary in the BMJ in 2000, under the title: ” Competing interests and controversy about third generation oral contraceptives. BMJ readers should know whose words they read.” [13 ] Not much has changed.
In the context of finding the safest oral contraceptive, a statement that ‘the benefits of oral contraceptives outweigh the risks’ is disingenuous, for it suggests the choice is between a contraceptive or no contraceptive. The choice, however, is between a safe and an unsafe oral contraceptive. The authors also do not seem to understand the difference between proving effectiveness and safety: while, for a drug, effectiveness needs to be proven, harm does not: reasonable doubt about harm is sufficient to render prescribing a drug irresponsible.
1. Vandenbroucke JP, Rosing J, Bloemenkamp KWM, Middeldorp S, Helmerhorst FM, Bouma BN, Rosendaal FR. New insights in oral contraceptives and venous thrombosis. N Engl J Med 2001; 344: 1527-1535.
2. Vasilakis-Scaramozza C, Jick H. Risk of venous thromboembolism with cyproterone or levonorgestrel contraceptives. Lancet 2001; 358: 1427-9.
3. Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009; 339: b2890.
4. Jick SS, Hernandez RK. 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. BMJ 2011; 342:d2151.
5. Rosendaal FR, Van Hylckama Vlieg A, Tanis BC, Helmerhorst FM. Estrogens, progestogens and thrombosis. J Thromb Haemost 2003; 1: 1371-80.
6. van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 2009; 339: b2921.
7. Rosing J, Tans G, Nicolaes GA, Thomassen MC, van Oerle R, van der Ploeg PM, Heijnen P, Hamulyak K, Hemker HC. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol 1997; 97: 233-8.
8. Tans G, van Hylckama Vlieg A, Thomassen MC, Curvers J, Bertina RM, Rosing J, Rosendaal FR. Activated protein C resistance determined with a thrombin generation-based test predicts for venous thrombosis in men and women. Br J Haematol 2003; 122: 465-70.
9. Rosing J, Middeldorp S, Curvers J, Christella M, Thomassen LG, Nicolaes GA, Meijers JC, Bouma BN, Büller HR, Prins MH, Tans G. Low-dose oral contraceptives and acquired resistance to activated protein C: a randomised cross-over study. Lancet 1999; 354: 2036-40.
10. van Vliet HA, Winkel TA, Noort I, Rosing J, Rosendaal FR. Prothrombotic changes in users of combined oral contraceptives containing drospirenone and cyproterone acetate. J Thromb Haemost 2004; 2: 2060-2.
11. Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589-93.
12. Farmer RD, Williams TJ, Simpson EL, Nightingale AL. Effect of 1995 pill scare on rates of venous thromboembolism among women taking combined oral contraceptives: analysis of general practice research database. BMJ 2000; 321:477-9
13. Vandenbroucke JP, Helmerhorst FM, Rosendaal FR. Competing interests and controversy about third generation oral contraceptives. BMJ readers should know whose words they read. BMJ 2000; 320: 381-2.
Competing interests: No competing interests
How can women benefit from choosing different forms of hormonal contraception? Most women have no idea that their symptoms are actually due to the Pill in the first place!
Even doctors often fail to know that oral contraceptives have been classified as Group 1 carcinogens.1
Progesterone dominant contraception, with or without oestrogens, causes numerous biochemical changes including increasing vascular endothelial growth factor and suppressing immune mechanisms.2
Progesterone use doubled the risk of HIV transmission for both male to female transmission and female to male transmission.3 Gollup and Stein think the weight of evidence calls for a discontinuation of progestin-dominant methods in the best interests of women.4
The relative risk of a venous thromboembolic event for users of an injectable progestin versus non-progestin users was found to be 2.67 (1.29 to 5.53).5 Progestin only studies may underestimate real risks due to shortage of control never-ever users of hormones.5
1 IARC Monographs Vol. 91. Combined Estrogen-Progestogen Contraceptives and Combined Estrogen-Progestogen Menopausal Therapy.2007;528 pages
2 Huijbregts RP, Helton ES, Michel KG, et al. Hormonal Contraception and HIV-1 Infection: Medroxyprogesterone acetate suppresses innate and adaptive immune mechanisms. Endocrinology. 2013;154:282-95.
3 Heffron R, Donnell D, Rees H, et al. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. The Lancet Infectious Diseases, 2012;12:19–26.
4 Gollub E, Stein Z. Living with uncertainty: acting in the best interests of women. AIDS Res Treat. 2012;2012:524936.
5 Mantha S. Krap R, Raghavan, Terrin N et al. Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis. BMJ;345:e4944.
Competing interests: No competing interests
We read with interest the Editorials by Frans M Helmerhorst and Frits R Rosendaal (1) attempting to show that an EMA review on hormonal contraception and thrombosis will be lengthy and not needed as “sufficient evidence is already available on which clinicians and regulatory agencies can base their decisions”.
On one hand, we agree with the authors regarding the fact that, as there are no new epidemiological data recently published on hormonal contraception and thrombosis, an EMA review is not needed; on the other hand, we do not agree with their conclusion “we can see no reason to use another type”of contraception except those containing levonorgestrel and ethinylestradiol. Each woman has her own specificity and clinicians, like ourselves, have to decide individually their prescription in accordance with the EMA recommendations, but also in line with the users’ profile.
In addition, we agree that the categorization of the pill based on progestogens is imprecise and incomplete and that the risk of venous thrombosis depends “on the dose of estrogen and the type of progestogen, even within generations”; however we wish to point out that an official classification acknowledged by all countries at the European level is essential.
For instance, in France the classification available is not used by other countries and it is based on chronological criteria. That being so, 4thgeneration (2) includes very diverse compounds: ethinylestradiol and natural estrogen pills, pills with progestogens derived from progesterone (chlormadinone acetate, nomegestrol acetate), from spironolactone (drospirenone) or from 19 nor-testosterone (dienogest). The present classification is not in line with the different pharmacological properties of the compounds which are likely to have also peculiar clinical properties (3). Moreover, such approach is confusing, mainly because we believe estradiol pills should be removed from any other previous category as the type of estrogen makes them potentially different from the ethynilestradiol containing pills. Furthermore, this classification implies a priori a level of risk, even though the real risk of thrombosis of some of the new combinations is not known.
That notwithstanding, WHO has recently established to modify the ATC code of the combined contraceptions with a clear differentiation between estradiol/estradiol valerate containing pills and ethinylestradiol containing pills. It is, indeed, conceivable that these estrogens are different because their liver impact on protein synthesis, including coagulation factors, is not the same.
Today, we do not have enough epidemiological data to determine the thrombosis risk of natural estrogen pills because they have been marketed very recently and their benefit/risk ratio, including the thrombosis risk, will be assessed in the forthcoming years, if these new pills will be prescribed in spite of the negative environment on hormonal contraceptives recently available. We should avoid to mix apples with oranges being aware that estradiol is known, even when it is administered orally, to have a lower impact on liver proteins. Such lower “estrogenicity” (4-6), i.e.measured by SHBG level changes, might be correlated to Activated Protein C sensitivity which in turn might be correlated to the VTE risk (7). On the other hand, the amount of estrogenicity of a specific pill, even containing natural estradiol in the attempt to reduce VTE risk, depends also on the level of androgenicity of the progestogen combined.
In conclusion, we suggest, in line with the new ATC code, to rather regard the pills as an association of a specific estrogen and a specific progestogen rather than categorize them in generations which are no more appropriate to the recent pharmaceutical developments.
The authors are listed alphabetically; they equally contributed to the letter after collegial discussion.
(1) Helmerhorst FM and Rosendaal FR. BMJ 2013; 346:f1464 doi
(3) Jamin C J Gynecol Obstet Biol Reprod 2012, 41: 103-4
(4) Gaussem P et al. Thromb Haemost 2011;105:560-7
(5) Mashchak CA et al. Am J Obstet Gynecol, 1982, 144:511-51
(6) Sitruk-Ware R. Maturitas, 2008, 61:151-7
(7) Tchaikovski SN, Rosing J. Thromb Res; 2010, 126:5-11
Competing interests: Nathalie Chabbert Buffet had a financial relationship (lecturer, member of advisory boards and/or consultant) with HRA, Teva/Theramex. Jan Gerris is member of an advisory board: TEVA. Christian Jamin had a financial relationship (lecturer, member of advisory boards and/or consultant) with Bayer, Besins, Effik, HRA, MSD and TEVA. Inaki Lete had a financial relationship (lecturer, member of advisory boards and/or consultant) with Bayer, MSD and TEVA. Paloma Lobo had a financial relationship (lecturer, member of advisory boards and/or consultant) with Bayer, Effik, HRA, MSD and TEVA. Rossella E. Nappi had a financial relationship (lecturer, member of advisory boards and/or consultant) with Bayer-Schering Pharma, Eli Lilly, HRA Pharma, Merck Sharpe & Dohme, Novo Nordisk, Pfizer Inc, and Teva/Theramex. Axelle Pintiaux had a financial relationship (lecturer, member of advisory boards and/or consultant) with TEVA.
In a recent editorial by Professors Helmerhorst and Rosendaal, the authors state that the risk of thrombosis (venous and arterial) is related to both the amount of Ethinyl Estradiol (EE) and progestogen type (1). Based on this observation, they opine that women should be prescribed contraception containing levonorgestrel and 30mcg of Ethinyl Estradiol (LNG/EE), and that the need for EMA review is obviated. We are in agreement with the authors on two points: firstly, that the risk of thrombosis is related directly to the dose of EE, and that an EMA review is not required. However, we disagree with the assertion that the progestogen type plays a significant role in thrombosis risk.
In reviewing the literature on thrombosis risk and progestogen type, we must return to the principles of evidence-based medicine and first consider the quality of the evidence being presented. Owing to the low-cost and ability to rapidly amass many woman-years of observation, retrospective studies, particularly those which rely upon administrative databases, are both popular and frequently cited (2,3). This study design is well-known to be fraught with methodological flaws, including, but not limited to, lack of validation of diagnosis, lack of control of confounding variables, and violation of time order by not restricting data to first-time users (4,5,6). In the cited case-control MEGA study (7), the selection of controls (partners of those with VTE) make risk interpretation confusing for patients, and 95% confidence intervals of Odds Ratios for DVT/PE (i.e. excluding arm DVTs) overlap across progestogen types.
The continued use of retrospective database studies may threaten the introduction and uptake of new and potentially superior contraceptive options, limiting options for women. Owing to the significant adverse risks to patients of unintended pregnancies resulting from pill scares, conclusions regarding progestogen type and thrombosis risk, particularly VTE, must be made based on the best available studies: those which are prospective, use appropriate comparators (new users with similar age and risk characteristics), and utilise active surveillance. Of the available prospective cohort studies, no differences in VTE risk between levonorgestrel and other progestogens has been demonstrated (8, 9, 10, 11). The Society of Obstetricians and Gynaecologists of Canada has recently conducted a review of the existing literature and has released two position statements affirming the comparable safety of third-generation, fourth-generation, and CPA/EE to other contraceptives, reiterating that “for most women, the benefits of [oral] contraception will outweigh the risks” (12, 13).
As family planning practitioners, we clearly wish to reduce the risk to patients both from unintended pregnancy and from contraceptive use. While the strategy proposed by the authors is interesting, it is not adequately evidence-based. Furthermore, we discourage the application of a “one-pill-fits-all” approach to contraception. Women currently benefit from a range of products (medication, dose and schedule) that allow them to balance their own benefits (contraceptive and non-contraceptive) against risk. Such a restrictive practice may be viewed as paternalistic, creating dissatisfaction with providers, a known risk factor for non-adherence (14). We hope that the EMA will carefully weigh the existing data in its review, and, in doing so, reassure women that oral contraceptives are safe (not risk-free) across the progestogen classes. In the interim, we must continue to provide patients with a range of tools to prevent pregnancy, and knowledge to assist in safe contraceptive decision-making.
1. Helmerhorst FM, Rosendaal FR. Is an EMA review on hormonal contraception and thrombosis needed? BMJ 2013;346:f1464.
2. Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 2011;343:d6423.
3. Sidney S, Cheetham TC, Connell FA, Ouellet-Hellstrom R, Graham DJ, Davis D, Sorel M, Quesenberry CP Jr, Cooper WO. Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users. Contraception. 2013;87:93-100.
4. Severinsen MT, Kristensen SR, Overvad K, Dethlefsen C, Tjønneland A, Johnsen SP. Venous thromboembolism discharge diagnoses in the Danish National Patient Registry should be used with caution. J Clin Epidemiol. 2010;63:223-8.
5. Grimes D. Epidemiologic research using administrative databases: Garbage in, garbage out. Obstet Gynecol 2010;116:1018-9.
6. Shapiro S. Combined hormonal contraceptives and the risk of venous and arterial thromboembolism and cardiovascular death: misuse of automated databases. J Fam Plann Reprod Health Care. 2013;39:89-96.
7. van Hylckama Vlieg A, Helmerhorst, FM, Vandenbroucke JP, Doggen CJM, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 2009;339:b2921
8. Dinger JC, Heinemann LA, Kühl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on Oral Contraceptives based on 142,475 women-years of observation. Contraception 2007; 75(5): 344–54.
9. Seeger JD, Loughlin J, Eng PM, et al. Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives. Obstet Gynecol 2007; 110(3): 587–93.
10. Dinger J, Assman A, Moehner S. Long-Term Active Surveillance Study for Oral Contraceptives (LASS): Impact of Oral Contraceptive Use on the Start of Antihypertensive Treatment. Pharmacoepidemiol Drug Saf 2010;19:S232.
11. Dinger J, Bardenheuer K, Moehner S. The risk of venous thromboembolism in users of a drospirenone-containing oral contraceptive with a 24-day regimen – results from the INAS-OC study. Fertil Steril 2009;94:S3.
12. Society of Obstetricians and Gynaecologists of Canada. Position Statement: Hormonal Contraception and Risk of Venous Thromboembolism (VTE). http://www.sogc.com/media/documents/medHormonalContraceptionVTE130219.pdf. Accessed March 26, 2013.
13. Society of Obstetricians and Gynaecologists of Canada. Position Statement: Diane-35 and risk of venous thromboembolism (VTE). http://www.sogc.com/media/documents/medDiane35VTE130219.pdf. Accessed March 26, 2013.
14. Rosenberg MJ, Waugh MS, Burnhill MS. Compliance, counseling, and satisfaction with oral contraceptives: A prospective evaluation. Fam Plann Perspect 1998;30:89-92.
Competing interests: Dr Costescu: Has previously received honoraria from Pfizer (Canada) and Bayer Healthcare (Canada). Dr Waddington: Has previously received honoraria from Bayer Healthcare (Canada), Merck (Canada), Pfizer (Canada), and Warner-Chilcott (Canada).
In their Editorial Professor Helmerhorst and Professor Rosendaal FR write that their recent network meta-analysis of all combined oral contraceptives (unpublished data) found that the risk of venous thrombosis depended on the dose of oestrogen and the type of progestogen, even within progestogen generations.1
In 1969 my BMJ paper, “Venous effects of oral contraceptives”, detailed that venous effects, including thrombosis and pulmonary embolism, varied with the hormone balance of different doses of the same progestogen with a constant dose of oestrogen or different doses of oestrogens with the same dose of different progestogens.2 Six increasing doses of norgestrel (levonorgestrel and an inactive isomer) plus a constant dose of oestrogen switched side effects from irregular bleeding, to venous complaints and dilated endometrial sinsuoids and thrombosis, then to headaches and increased endometrial arteriolar development, and, with the highest progestogen doses, to depressive mood changes with loss of libido and high endometrial monoamine oxidase activity.3,4,5,
My BMJ Editorial (anonymous at that time) revealed that varying progestogen/oestrogen doses or types of oral contraceptives merely changed which effects became most prominent.6
Helmerhosrt and Rosendaal recommend use of oral contraceptives containing levonorgestrel and the lowest tolerable dose of oestrogen as other progestogens have a higher risk of venous thrombosis. However it is suicide, rather than thrombosis, which is the commonest cause of death in young women.
Antidepressant use is commonest in 16-19 year olds, especially if they are taking “newer” contraceptives which oddly enough includes an Intra Uterine System containing levonorgestrel.8-10
It is wise to consider all of the many serious conditions caused by use of hormonal contraception including the increased risks of suicide and breast cancer.
1 Frans M Helmerhorst FM, Rosendaal FR. Is an EMA review on hormonal contraception and thrombosis needed? BMJ2013;346:f1464
2 Grant ECG. Venous effects of oral contraceptives. BMJ. 1969;2:73-77.
3 Grant ECG. Hormone balance of oral contraceptives. JObstetGynaecolBritComm 1967;74:908-18.
4. Grant ECG. Relation between headaches from oral contraceptives and development of endometrial arterioles. BMJ 1968;3:402-5.
5 Grant ECG, Pryce Davies J. Effect of oral contraceptives on depressive mood changes and on endometrial monoamine oxidase and phosphatases. BMJ 1968;3:777-80.
6 Changing oral contraceptives. BMJ 1969;4:789-91.
7 Lindberg M, Foldemo A, Josefsson A, Wiréhn AB.Eur J Contracept Reprod Health Care. 2012 Apr;17(2):106-18. Epub 2012 Mar 4. Differences in prescription rates and odds ratios of antidepressant drugs in relation to individual hormonal contraceptives: a nationwide population-based study with age-specific analyses.
8 Wiréhn AB, Foldemo A, Josefsson A, Lindberg M. Use of hormonal contraceptives in relation to antidepressant therapy: A nationwide population-based study. Eur J Contracept Reprod Health Care. 2010 Feb;15(1):41-7.
9. Grant ECG. Re: Newer non-oral hormonal contraception. BMJ (Published 17 February 2013)
Competing interests: No competing interests