Oral contraceptives and venous thromboembolism
BMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b3164 (Published 13 August 2009) Cite this as: BMJ 2009;339:b3164
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Helmerhorst and Rosendaal have asked recently, “Is an EMA review on hormonal contraception and thrombosis needed?” They recommend only levonorgestrel oral contraceptives containing the lowest tolerable dose of oestrogen because other progestogens have more risk of venous thrombosis.1
However suicide, not thrombosis, was the commonest cause of death in young women at the start of the RCGP study.2 Antidepressant use is now commonest in 16-19 year olds, especially if they are taking “newer” contraceptives which includes an Intra Uterine System containing only levonorgestrel.3,4
My 1969 BMJ Editorial summarized the results of the FPA oral contraceptive trials. It was clear that varying progestogen and/or oestrogen doses or types of oral contraceptives just changed which vascular and mood changes became most frequent.5
In a 2009 case-control study 17% of women with stroke under age 50 were positive for lupus anticoagulant (OR, 43.1). The risk was further increased by taking oral contraceptive (OR, 201.0) or smoking (OR, 87.0).6 Women attending a migraine clinic who were taking oral contraceptives had 2.5 times more migraine attacks than women who only smoked. Stopping both reduced the number of migraine attacks ten-fold.7
Also, the WHI and MWS HRT results have proved there is more risk of breast cancer with progestogens than with oestrogens. Increases in breast cancer closely match the changes in progestogen and oestrogen prescribing since 1962. Figure 1
All the many serious life-threatening conditions caused by hormonal contraception need to be considered. The options for changing hormonal contraceptives are running out.
1 Helmerhorst FM, Rosendaal FR. Is an EMA review on hormonal contraception and thrombosis needed? BMJ 2013;346:f1464.
2 Royal College of General Practitioners. Oral Contraceptives and Health. 1974 Pitman Medical, London.
3 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;15:41-7.
4. Lindberg M, Foldemo A, Josefsson A, Wirehn AB. 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. The European journal of contraception & reproductive health care : the official journal of the European Society of Contraception. 2012;17(2):106-18. Eur J Contracept Reprod Health Care. 2012 Apr;17(2):106-18. Epub 2012 Mar
5 Urbanus RT, Stiegerink B, Roest M, Rosendaal FR, et al. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study; a case-control study. Lancet Neurol 2009;8:998-1005.
6 Grant ECG. Oral contraceptives, smoking, migraine and food allergies. Lancet 1978;2:581-2
7 Changing oral contraceptives. BMJ 1969;4:789-91.
Competing interests: No competing interests
The normal levels of oestrogen (estradiol primarily) range in blood as 20-400 picogram per ml. The content of oestrogens in combined oral contraceptives ranges from 20 micrograms to 50 micrograms per tablet. In a blood volume of 4 litres (4000ml) the concentration of oestrogen would be 20 microgram X 10X10X10X10X10X10 (i.e 10 raised to power 6) X 1/4000 ml = 5000 picogram/ml of blood which is very high concentration to inhibit the ovulation. So, in order to avoid side effects e.g. VTE, breast cancer, weight gain we can easily reduce the amount further.
Competing interests: No competing interests
Dr Dunn's editorial on oral contraceptive use and venous
thromboembolism prompted debate about cardiovascular risk factors and
contraindications to use of the combined oral contraceptive pill (COC).[1]
The confusion is not surprising given the various sources of information
on contraceptive prescribing which often give inconsistent advice.
We would like to raise awareness of a recently updated document which
provides guidance on contraindications to use of contraception. The UK
Medical Eligibility Criteria for Contraceptive Use (UKMEC)[2] is a set of
evidence-based recommendations which have been adapted from WHO guidance
(WHOMEC).[3] UKMEC guidance has been adopted as accepted practice by UK
specialists working in the field of sexual and reproductive health.
However the majority of contraceptive prescribing occurs in general
practice where UKMEC guidance is possibly less well known.
The medical eligibility criteria classify the use of specific
contraceptive methods by individuals with a particular medical condition
(or in certain circumstances) into four risk categories (Table 1).
Dr Dunn stated that obesity is not a contraindication to using the
[combined] pill.[1] At the time of publication this was incorrect in the
context of UK clinical practice. The use of combined hormonal
contraception (pills, patch or vaginal ring) by a woman with a body mass
index (BMI) > 39 kg/m2 was considered an unacceptable health risk
(UKMEC category 4).[4]
Both WHOMEC and UKMEC guidance have been reviewed within the past
year. WHOMEC 2009 continues to advise a MEC category 2 (benefits outweigh
the theoretical or proven risks) for combined hormonal contraceptive (CHC)
in women with BMI > or = 30 kg/m2. [3] In adapting MEC for UK practice,
the consensus group took into account the increased risk of VTE associated
with obesity, while recognising that the absolute risk remains low.
Therefore, UKMEC 2009 (table 2) advises that for women with BMI 30 to 34
kg/m2 the benefits of using CHC outweigh the risks (UKMEC category 2), and
for women with BMI > or = 35 kg/m2 the theoretical or proven risks of
using CHC generally outweigh the advantages (UKMEC category 3).[2]
Provision of a method to an individual with a category 3 condition would
require expert clinical judgement and/or referral to a specialist
contraceptive provider.
Development of UKMEC was funded by a grant from the Department of
Health. It is intended as a reference document for all health care
professionals providing contraceptive advice and/or treatment for women
and men in the UK. UKMEC 2009 is available on the website of the Faculty
of Sexual and Reproductive Healthcare (www.fsrh.org).
Yours sincerely
Dr Louise Melvin
Director
Clinical Effectiveness Unit of the Faculty of Sexual & Reproductive
Healthcare,
Sandyford,
2/6 Sandyford Place,
Glasgow
G3 7NB
Dr Susan Brechin
Consultant in Sexual & Reproductive Health & Honorary Senior
Clinical Lecturer
NHS Grampian Community Health Partnership
Square 13 Centre for Family Planning and Reproductive Health,
13 Golden Square,
Aberdeen
AB10 1RH
1. Dunn N. Oral contraceptives and venous thromboembolism. BMJ
2009; 339: B3164.
2. Faculty of Sexual & Reproductive Healthcare Care. UK
Medical Eligibility Criteria for Contraceptive Use. 2009
[http://www.fsrh.org/admin/uploads/UKMEC2009.pdf] Accessed 2 December 2009
3. World Health Organization. Medical Eligibility Criteria for
Contraceptive Use. Fourth Edition. 2009.
[http://whqlibdoc.who.int/publications/2009/9789241563888_eng.pdf]
Accessed 2 December 2009
4. Faculty of Sexual & Reproductive Healthcare Care Clinical
Effectiveness Unit. UK Medical Eligibility Criteria for Contraceptive Use.
2005/6 [http://www.fsrh.org/admin/uploads/archive/UKMEC2005_06.pdf]
Accessed 2 December 2009
Competing interests:
Dr Susan Brechin coordinated the development of UKMEC 2009
Competing interests: No competing interests
Doctor Howman is quite right in that the choice of low-dose oestrogen
pills in the UK is pretty restricted. Also there are problems with these
pills with breakthrough bleeding, as well as the narrow margin for error
in remembering to take them (as she points out). Clearly these pills will
not be suitable for everyone, and anyway the theoretical advantage in
safety regarding VTE is small in absolute terms . The well tried and
tested brands of Ovranette/Microgynon 30 or Brevinor are still pretty
good choices!
Competing interests:
None declared
Competing interests: No competing interests
Further to Dr Dunn's interesting editorial, a couple of points spring
to mind.
Firstly, as far as I am aware there isn't a low dose pill with
levonorgestrol which is easily available in the UK, leaving loestrin 20 as
the only low dose pill containing levonorgestrel or norethisterone.
Also as per FFPRHC guidance
(http://www.ffprhc.org.uk/admin/uploads/MissedPillRules%20.pdf), barrier
methods need to be used for a week if two low dose pills are missed or
three higher dose pills. Prescribing low dose pills as first line may
therefore have implications for efficacy, perhaps particularly in younger
people or those who have a tendency to forget to take pills.
Competing interests:
None declared
Competing interests: No competing interests
Thanks to Dr Massey for her response. The web address which she
references is very useful , but is careful in its wording. On obesity, a
BMI of 30-34.9 ( classified as obese) is not classified as a contra-
indication to COC use ("advantages generally outweigh the risks"), whereas
35, or >, is ("risks usually outweigh the advantages"). The majority of
obese women of child-bearing age will fall into the first category.
On family history, I agree entirely that accuracy of history on familial
VTE is important, and age, as well as closeness of relationship, should
theoretically be taken into account. However as a rule of thumb in
clinical situations, I would be very loathe to prescribe the COC to any
woman who describes any sort of positive FH, because accurate histories of
this type are difficult to obtain (DVT can be silent, or missed as a
diagnosis, and the patient may have lost touch with members of her
family).
Competing interests:
None declared
Competing interests: No competing interests
In response to Nick Dunn's article, there are two points which I
think require the specifics to be spelt out, otherwise further spin of
half truths and inaccuracies carries on.
Family History
Patients with a family history of VTE in a first degree relative under the
age of 45 should not use the combined pill, but with all other family
history the use may be acceptable.
Obesity
In a woman with a body mass index of over 35, use of the combined pill
poses risks greater than benefits - not quite the same as saying obesity
is not a contraindication.
The UK Medical Eligibility Criteria for Contraceptive use 2005/6
http://www.ffprhc.org.uk/admin/uploads/298_UKMEC_200506.pdf is the best
source of information for safe prescribing.
Competing interests:
None declared
Competing interests: No competing interests
Although there were several reports of early oral contraceptives
increasing blood viscosity, there has been no comments about modern
contraceptives in this regard. But as smoking increases blood viscosity,
if as Dr.Godsland comments it is a risk factor for arterial disease in
users of oral contraceptives, then maybe the contraceptives are increasing
blood viscosity. This would raise the question as to whether or not the
effects of altered blood rheology are being interpreted as arterial
disease.
Competing interests:
None declared
Competing interests: No competing interests
In his Editorial (1) on the two studies of venous thromboembolism in
combined oral contraceptive (COC) users (2,3), recently published in BMJ,
Nick Dunn makes the sensible point that the risk background for thrombosis
in oral contraceptive users is sufficiently low “... to enable some
negotiation when dealing with individual patients, for whom personal
experiences or prejudices about side effects should be considered, and a
pill containing a recent progestagen or a higher dose of oestrogen may be
more appropriate.” I was, nevertheless, rather shocked to see his
concluding sentence begin, “Contrary to popular belief, smoking is not a
risk factor for venous thromboembolism...” Whilst I am sure this was not
intended, there could be the implication that cigarette smoking is no more
a health issue for COC users than it is for anyone else. Smoking is a
serious issue for COC users in relation to its potential for augmenting
their increased risk of arterial disease. It is disturbing that neither
the Editorial (1) nor the paper by Van Hylckama Vlieg and colleagues from
the Leiden group (2) mentioned arterial disease. Whilst arterial disease
is much rarer in COC users than venous thromboembolism, its consequences
can be considerably more serious. One of the original justifications for
introducing new progestagens in the 1980s was the concern generated in the
1970s by repeated reports of increased risk of myocardial infarction in
COC users. The previous observation by the Leiden group (4) that
levonorgestrel COC significantly increase risk of myocardial infarction
whereas desogestrel COC do not, despite these progestagens being combined
with the same oestrogen dose, should have been mentioned to provide a more
balanced perspective.
Ian Godsland, PhD,
Wynn Reader in Human Metabolism,
Endocrinology and Metabolic Medicine,
Imperial College London,
London UK.
1) Dunn N. Oral contraceptives and venous thromboembolism. BMJ
2009;339:b3164
2) Van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen
CJM, Rosendaal FR. Effects of oestrogen dose and progestogen type on
venous thrombotic risk associated with oral contraceptives: results of the
MEGA case-control study. BMJ 2009:339:b2921
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) Tanis BC, van den Bosch MA, Kemmeren JM, Cats VM, Helmerhorst FM,
Algra A, van der Graaf Y, Rosendaal FR. Oral contraceptives and risks of
myocardial infarction. New England Journal of Medicine 2001;345:1787-1793
Competing interests:
No pharmaceutical company involvements for >5years
Competing interests: No competing interests
Re: Oral contraceptives and venous thromboembolism
On second thoughts we realized that the estradiol (the hormone) would get distributed in the whole body fluids (The ECF or extra cellular fluid which is 15 litres), rather than just blood alone. So instead of blood we have to calculate the estradiol content in the larger compartment, i.e. ECF. So we replace the amount of 4000 ml by 15,000 ml (inclusive of blood volume) and the normal values of estrogen measured in blood would be:
20 microgram (the content of oestrogens in combined oral contraceptives ranges from 20 micrograms to 50 micrograms per tablet)
X 10X10X10X10X10X10 (i.e 10 raised to power 6)
X 1/15,000 ml (the ECF) = 1333 picogram/ml.
The normal levels of oestrogen (estradiol primarily) range in blood as 20-400 picogram per ml.
SO EVEN WITH THIS CALCULATION THE AMOUNT OF OESTROGEN IS MORE THAN 3 TIMES OF HIGHEST VALUE OF PHYSIOLOGICAL AMOUNT, VIZ. 400 PICOGRAM PER ML. PRESENT IN BODY. And this is stil a high concentration to inhibit the ovulation. So, in order to avoid side effects e.g. VTE, breast cancer, weight gain we can easily reduce the amount further.
Competing interests: No competing interests