This chapter should be cited as follows:
Lidegaard, &, Glob. libr. women's med.,
(ISSN: 1756-2228) 2015; DOI 10.3843/GLOWM.10388
This chapter was last updated:
July 2015

Thrombotic Risks with Hormonal Contraception

Øjvind Lidegaard, MD, DrMedSci
Clinical Professor in Gynecology & Obstetrics, Department of Gynecology, Rigshospitalet, Faculty of Health Science, University of Copenhagen, Denmark

INTRODUCTION

Hormonal contraception includes oral contraceptives, contraceptive patches, implants, vaginal ring, intrauterine devices, and intramuscular depot. These different routes of administration may be further subdivided into combined products with both estrogen and progestin, and progestin only products. The combined products often exist with different doses of hormones, and the time they have been used seems to modify their influence on the risk of thrombosis, at least for some combinations.

Considering thrombotic diseases, these include on the venous side deep venous thrombosis and pulmonary embolism, together venous thromboembolism, and on the arterial side myocardial infarction and thrombotic stroke. Female sex hormones (natural or artificial) have a differential influence on these clinical end points.

Therefore, it is not possible in a simple way to express the influence of hormonal contraception on the risk of developing a thrombotic disease.

Combined estrogen–progestin oral contraceptives have been linked with an increased risk of vascular disease since they were first marketed in 1960. It was quickly recognized that the vascular risks of oral contraceptives were related to the estrogen dose, and formulations were altered to lower risk.

Recently, carefully conducted studies on the influence of hormonal contraception on the risks of venous thromboembolism, myocardial infarction, and stroke clarify the risks of the newer products, now in widespread use worldwide. This review discusses these recently conducted studies including the effect of the progestin type in modifying the risks of vascular disease in users of hormonal contraption.

In this report we operate with three classes of products according to their influence on the risk of venous thrombosis. High risk products imply a relative risk of venous thrombosis of five or more, low risk products confer a relative risk of thrombosis of 1.5–4 and no-risk products a relative risk of less than 1.5.

Abbreviations used:

CHC = combined hormonal contraception

VTE = venous thromboembolism = deep venous thrombosis + pulmonary embolism

EE = ethinylestradiol

 

SUMMARY OF EVIDENCE

  • Progestin only products (oral and non-oral) do not increase the risk of any type of thrombosis.
  • Combined products influence the risk of venous thromboembolism and pulmonary embolism more than the risk of the arterial end points myocardial infarction and thrombotic stroke.
  • Products with a high dose of estrogen imply a higher risk of thrombosis than products with a low dose.
  • For some combination products, the risk of venous thrombosis decreases by length of use.
  • Today, after the withdrawal of high estrogen pills from the market, the progestin type in combined products is the key parameter to differentiate between products with a relative high and a low risk of venous thromboembolism, respectively.
  • Combined oral products with desogestrel, gestodene, drospirenone or cyproterone acetate (high risk products) confer a six fold increased risk of venous thromboembolism as compared with non-users, and about twice the risk as compared with users of products with norethisterone, levonorgestrel or norgestimate (low risk products).
  • Transdermal patches and vaginal ring contraception confer a six fold increased risk of venous thromboembolism as compared with non users and belong to high risk products.
  • The risk of thrombotic stroke and myocardial infarction is increased 50–100% with use of combined products, with little difference in risk between products with different progestins.
  • Women with other risk factors for venous thromboembolism, such as previous thrombosis, genetic predispositions, immobilization, adiposity, polycystic ovary syndrome, and varicose veins should not use high risk products, and be careful to use low-risk products. Such women may use progestin only products (whether oral or non-oral) without increasing their risk of venous thromboembolism.
  • Women with risk factors for arterial thrombosis, such as smoking, hypertension, diabetes, hyperlipidemia, migraine with aura, and age above 35 years should primarily consider progestin only products, and should be careful to use combined products, oral as well as non-oral.
  • The absolute risk of thrombotic complications depends first of all on age, whereas the relative risk of thrombotic complications with use of hormonal contraception generally is independent of age.
  • The case–fatality rate among women with thrombotic complications is about 1% for venous thromboembolism, 1.5% for thrombotic stroke and about 10% for myocardial infarction.
  • All women who are prescribed a combined hormonal contraceptive product should be informed about the risk of venous thromboembolism, and the symptoms of such a thrombosis in order to ensure an early diagnosis and treatment.

HORMONAL CONTRACEPTIVES

VENOUS THROMBOEMBOLISM IN YOUNG WOMEN

The incidence of venous thromboembolism in non-pregnant women who are not using hormonal contraception increases from 0.7 per 10,000 women-years in women 15–19 years old to 5.8/10,000 women-years in women 45–49 years old, or about eight fold through fertile age.1

At the same time has the incidence has increased about 5% per calendar year over recent decades. This increase is influenced by improvements in diagnostic accuracy and the increasing proportion of adipose women. Adiposity is a well established risk factor of VTE, together with family disposition, varicose veins, coagulation disorders such as activated protein C (APC)-resistance or factor V Leiden mutation, immobilization, pregnancy and other factors causing physical pressure on pelvic or limb veins.

About two-thirds of venous thromboembolism is deep venous thrombosis, and one third pulmonary embolism (with or without detected deep venous thrombosis).

 

VENOUS THROMBOEMBOLISM AND HORMONAL CONTRACEPTION

 

The influence of hormonal contraception on the risk of venous thromboembolism has been continuously debated since the 1960s. The results of the most important studies assessing specific product types and specifying the applied reference group are listed in Table 2.

Table 2 Relative risk of venous thromboembolism in current users of different combined hormonal contraceptives as compared with non-users unless otherwise specified

Study
First author

Data
sampling
period

Venous thrombosis
Number

 CHCs with
levonorgestrel

RR (95% CI)

 CHCs with
desogestrel
/gestodene

RR (95% CI)

 CHCs with
drospirenone
RR (95% CI)

 Blomenkamp2 1988–1992 126 3.8 (1.7–8.4) 8.7 (3.9–19.3) —
 WHO3, 4  1989–1993 433 3.6 (2.5–5.1) 7.4 (4.2–12.9) —
 Jick5 1991–1994 80 1 (reference) 1.8 (1.0–3.2) —
 Spitzer6 1991–1995 471 3.7 (2.2–6.2) 6.7 (3.4–13.0) —
 Lewis7 1993–1995 502 2.9 (1.9–4.2) 2.3 (1.5–3.5) —
 Farmer8  1991–1995 85 3.1 (2.1–4.5)

5.0 (3.7–6.5)

 —
 Todd9   1992–1997 99 1 (reference) 1.4 (0.7–2.8) —
 Bloemenkamp10 1994–1998 185 3.7 (1.9–7.2) 5.6 (not given) —
 Parkin11  1990–1998 26 5.1 (1.2–21.4) 14.9 (3.5–64.3) —
 Lidegaard12  1994–1998 987 2.9 (2.2–3.8) 4.0 (3.2–4.9) —
 Dinger13  2000–2004 118 1 (reference) 1.3 (na) 1.0 (0.6–1.8)
 Vlieg14 1999–2004 1524 3.6 (2.9–4.6)

 7.3 (5.3–10.0)
/5.6 (3.7–8.4)

 6.3 (2.9–13.7)
 Lidegaard15  1995–2005 4213 2.0 (1.8–2.3) 3.6 (3.3–3.8) 4.0 (3.3–4.9)
 Dinger16   2002–2008 680 1 (reference) na 1.0  (0.6–1.8)
 Parkin172002–2009 61 1 (reference) na 2.7 (1.5–4.7)
 Jick18  2002–2008 186 1 (reference) na 2.8 (2.1–3.8)
 Lidegaard1  2001–2009 4246 2.2 (1.7–2.8) 4.2 (3.6–4.9) 4.5 (3.9–5.1)
     Confirmed only 2001–2009 2707 2.9 (2.2–3.8) 6.8 (5.7–8.1) 6.3 (5.4–7.5)
 FDA Kaiser19 2001–2007 625 1 (reference) na 1.5 (1.2–1.9)
 Gronich20  2002–2008 518 1 (reference) 1.4 (0.9–2.1) 1.7 (1.0–2.7)
 Lidegaard21 2001–2010 5287 3.2 (2.7–3.8) 6.5 (4.7–8.9)* na
 Dinger22 2005–2010 162 1 (reference) na 0.8 (0.5–1.6)
Vinogradova23
 2001–2013 10,562 1 (reference)
 6.2 (5.0–7.7) 6.1 (4.7–7.8)

* Vaginal ring with the third generation progestin etonogestrel.

 

In all these 22 studies an increased risk of VTE was found with use of CHC. The risk has only decreased slightly over recent decades, despite the reduction in the dose of estrogen used in the pills (Table 2). The relative risk of VTE with use of CHC with levonorgestrel has been found to be about three in newer studies when compared with non-users.

Of 15 studies specifically assessing the risk in users of CHC with desogestrel or gestodene, 14 found a higher risk with use of these products when compared with use of CHC with levonorgestrel. The difference was significant in 10 of the 14 studies. Of five studies not demonstrating a significant difference, two were re-analyses7, 10 of primary studies demonstrating a significant difference,6, 8 while one study by Dinger et al. did not find any difference.13 The two re-analyses do not appear more statistically robust than the analyses in the primary studies. In a large study with validated end-points, the rate ratio between CHC with desogestrel versus levonorgestrel was 2.2 (1.7–2.8)1 and 1.8 (1.5–2.1).23 

Similarly, of 11 studies specifically assessing the risk of VTE in users of CHC with drospirenone versus users of CHC with levonorgestrel, seven found significant differences, three (all by Dinger et al.) showed no difference.13, 16, 22 In all eight studies demonstrating a difference, the rate ratio of VTE between users of CHC with drospirenone vs. levonorgestrel was 1.5–2.8, and the relative risk as compared with non-users was 6.3 in both the large Dutch14 and the Danish1 studies, and 6.1 in the new large British study.23

The studies demonstrating risk differences between CHC with different progestins are generally methodologically more transparent and more robust than those demonstrating no difference, especially concerning exclusion of women with predispositions for VTE.24 

All studies except one agree that the risk of VTE in users of CHC with desogestrel or gestodene is the same as in users of CHC with drospirenone.1, 13, 14, 15, 22, 23 Gronich et al. found a 43% (1.2–1.8) higher risk of VTE in users of CHC with drospirenone compared with users of CHC with desogestrel, and a rate ratio of 1.7 (1.0–2.7) when compared to CHC with levonorgestrel.20

The reason for the differential influence on the risk of VTE from different CHC seems to be explained by a direct influence on the coagulation process, and is also indicated by a differential influence on sex hormone binding globulin, a surrogate marker of VTE. 25, 26, 27

Table 3 summarizes the results for different specific product groups, stratified according to estrogen dose, progestin type and route of administration.

Table 3       The relative risk of venous thromboembolism in current users of different types of hormonal contraception according to estrogen dose, progestin type and route of administration

Estrogen
dose

NorethisteroneLevonorgestrelNorgestimate 

Desogestrel or
etonogestrel

GestodeneDrospirenone

Cyproterone
acetate
Combined hormonal contraception
 50 µg EEHigh risk
High risk
 — —
 30–40 µg EE Low risk
Low risk Low risk High risk High riskHigh riskHigh risk
 20 µg EE Low riskLow risk —High riskHigh riskHigh risk —
 E2 Limited data – E2V DNG — E2 NOMAC
 —
 Non oral — High risk – patch High risk – vaginal ring
 — —
Progestin only contraception
 Oral No risk
  No risk NA  No risk – desogestrel
 —
 Non oral  No risk – MPA--Depot No risk – LNG-IUS NA No risk – implant

— no data available
No risk, RR<1.5; Low risk, RR 1.5–4; High risk, RR ≥5
E2, estradiol (natural estrogen); E2V, estradiolvalerate; DNG, dienogest; NOMAC, nomegestrol; EE, ethinylestradiol (synthetic estrogen); MPA, medroxyprogesterone acetate

 

The relative risk during the first year is about 50% higher than after the first year. After 3 years, the relative risk is stable and increased with the figures indicated.

 

Women at risk of venous thromboembolism

About 10% of women (and men) are genetically predisposed for VTE. The most frequent condition is resistance to the anti-clotting effect of activated protein C (APC resistance), which increases the risk of VTE about eight times. This condition is caused by a mutation, the so called Leiden factor V mutation.

Most often, the combination of risk factors confer a relative risk of VTE corresponding to a multiplication of the relative risk of each risk factor. Thus, if a low risk CHC increases the risk of VTE three times, and this product is used by a women with a genetic APC-resistance, such a women will have a relative risk of VTE of 3 x 8 = 24, as compared with non-users without such a genetic predisposition.

A woman at 20 years has a baseline risk of VTE of 1 in 10,000 years. If she uses a low-risk hormonal contraceptive product, her absolute risk will be 3 per 10,000 years. If she at the same time has a Leiden factor V mutation, her absolute risk will be 24 per 10,000 years, and if she uses the product for 10 years, the absolute risk will be not 240 per 10,000 years, but about 300 per 10,000 years, because the risk increases for each year she gets older. An absolute risk of 300 per 10,000 years is 3 per 100 years. An absolute risk of a VTE of 3% will be a too high risk for a majority of women. If she was 30 years instead, her absolute risk after 10 years use would be about 6%.

Therefore, women with known risk factors of VTE are advised to be reluctant to use CHC. The relative risk of VTE with different dispositions is as follows: previous thrombosis: >5; Leiden factor V mutation (heterozygous): 6; pregnancy with delivery on average: 8; adiposity: 2–3; varicose veins: 2; and immobilization 2–5 depending on how long time you are immobilized. Family disposition (first degree relatives with VTE before their 50th year) doubles your risk of VTE. Women with such dispositions are generally recommended to use progestin only contraception, which does not increase the risk of VTE.  

 

 

THROMBOTIC STROKE AND MYOCARDIAL INFARCTION IN YOUNG WOMEN

The overall incidence rate of a first thrombotic stroke and myocardial infarction in women of reproductive age is 3 and 1 per 10,000 years, respectively. Both arterial end points have a steep increasing incidence rate with increasing age: thrombotic stroke thus increases from 0.3 per 10,000 years in women 15–19 years old, to 6.4 per 10,000 years in women 45–49 years old, more than a 20 fold increased risk with increasing age.28

The incidence rate of myocardial infarction increases from 0.04 per 10,000 years in women 15–19 years old to 3.8 per 10,000 years in women 45–49 years old, a 100 fold exponential increase with increasing age.

Thus, in women below 30 years, venous thromboembolism is more frequent than the arterial end points, whereas among women above 30 years, thrombotic stroke and myocardial infarction are more frequent than the venous complications.

The mortality in young women with a first thrombotic stroke is about 1.5%, and after a first myocardial infarction about 10%, but the survivors have more often lasting repercussions after their arterial thrombosis than after a venous thromboembolism. 

Risk factors for arterial thrombosis include previous arterial thrombosis, smoking, hypertension, diabetes, hyperlipidemia, heart arrhythmia, and shorter duration of education.28 

For thrombotic stroke each of the risk factors roughly doubles the risk, while for myocardial infarction smoking implies a relative risk of four, even more with heavy smoking, and diabetes a relative risk of five.

In case of exposure for several risk factors, one has to multiply the relative risk of each risk factor to achieve the combined effect.

HORMONAL CONTRACEPTION, THROMBOTIC STROKE AND MYOCARDIAL INFARCTION

Table 4 lists newer studies assessing the risk of thrombotic stroke in users of different types of hormonal contraceptives, and Table 5 the corresponding studies on myocardial infarction.

It appears that CHC in general confer less risk of the arterial complications than of VTE.

 

Table 4 Relative risk (RR) of thrombotic stroke in recent studies according to exposure to different types of  combined hormonal contraceptives. Reference: Non-users of hormonal contraception.

First author

year (ref)

Sampling

Design

N

CHC type

RR

95% CI

period

EE dose/progestin type

Poulter, WHO, 199929

1989–1993

Case–control

489

30–40 µg/levonorgestrel

2.7

1.8

4.1

 

 

 

 

30 µg/3rd generation

1.8

0.6

5.2

Heinemann, 199830

1993–1996

Case–control

220

30–40 µg/levonorgestrel

2.7

1.5

4.6

   

 

 

30 µg /3rd generation

3.4

1.9

6.4

 

 

 

 

3rd versus levonorgestrel

1.3

0.7

2.4

Swartz,199831

1991–1995

Case–control

171

20–30 µg/norethindrone

1.1

0.5

2.3

 


 

 

 

30–40 µg/levonorgestrel

1.0

0.3

3.6

Lidegaard, 200232

1994–1998

Case–control

626

30–40 µg/levonorgestrel

2.2

1.6

3.0

 

 

 

 

30 µg/3rd generation

1.4

1.0

1.9

Lidegaard,
201228

1995–2009

Cohort

3311

30–40 µg/levonorgestrel

1.6

1.4

1.9

       

35 µg/norgestimate

1.5

1.2

1.9

       

30 µg/desogestrel

2.2

1.8

2.7

       

20 µg/desogestrel

1.6

1.3

1.9

       

30 µg/gestodene

1.8

1.6

2.0

       

20 µg/gestodene

1.7

1.4

2.2

       

30 µg/drospirenone

1.7

1.3

2.2

 

 

 

 

20 µg/drospirenone

0.9

0.2

3.6

Gronich, 201120

2002–2008

Cohort

499

30–40 µg/levonorgestrel

1

Reference

 

     

20–30 µg/3rd generation

1.0

0.7

1.4

 

 

 

 

20–30 µg/drospirenone

0.9

0.6

1.3

3rd generation, CHC with desogestrel or gestodene; EE, ethinylestradiol

The more recent studies have found less influence on thrombotic stroke than the earlier studies, perhaps owing to a more effective exclusion of predisposed users by time. While middle dose CHC with desogestrel or gestodene may double the risk, the other combinations and all the low-dose combinations (20 µg estrogen) increases the risk about 50%, with no consistent difference according to the progestin type.  

For myocardial infarction (Table 5) similar results were demonstrated, with relative risks among current users of CHC of between 1.5 and 2.0 for low and middle dose products, and again with no consistent difference according to progestin type.

 

Table 5 Relative risk (RR) of myocardial infarction or cardiovascular disease (CVD) in users of different combined hormonal contraceptives in newer studies. Reference non-users.

First author

Year (ref)

End point

Design

N

CHC type

RR

95% CI

EE dose / progestin type

Stampfer, 198833

CVD death, MI non-fatal

Cohort

485

Current, all types

2.5

1.3

4.9

   

Lewis, 199734

Non-fatal MI

Case–control

182

Current all types

2.2

1.3

3.8

     

 

30–40 µg/levonorgestrel

3.0

1.5

14.3

 

 

 

 

30–40 µg/3rd generation

0.8

0.3

2.4

WHO, 199735

Non-fatal MI

Case–control

368

Current, all types

5.0

2.5

9.9

     

 

30–40 µg/levonorgestrel

1.6

0.5

5.5

 

 

 

 

30–40 µg/3rd generation

1.0

0.1

7

Sidney, 199836

Non-fatal MI

Case–control

271

Current (all types)

0.9

0.4

2.2

 

 

 

 

Dunn, 199937

Non-fatal MI

Case–control

448

Current, all types

1.4

0.8

2.5

     

 

30–40 µg/levonorgestrel

1.1

0.5

2.3

 

 

 

 

20–30 µg/3rd generation

2.0

0.9

4.4

Dunn, 200138

Fatal MI

Case–control

110

30–40 µg/levonorgestrel

2.9

1.2

6.8

 

 

 

 

20–30 µg/3rd  generation

0.8

0.3

2.8

Rosenberg, 200139

Non-fatal MI

Case–control

627

Current, all types

1.3

0.8

2.2

     

 

30–40 µg/norethindrone

2.5

1.1

5.5

     

 

30–40 µg/levonorgestrel

1.6

0.5

5.2

 

 

 

 

20–30 µg/3rd generation*

1.5

0.3

7.7

Tanis, 200140

Non-fatal MI

Case–control

248

Current, all types

2.0

1.5

2.8

     

 

30–40 µg/levonorgestrel

2.5

1.5

4.1

 

 

 

 

20–30 µg/3rd generation

1.3

0.7

2.5

Margolis, 200741

All MI

Cohort

214

Current, all types

0.7

0.4

1.4

 

Lidegaard, 201228

Fatal and

Cohort

 1,725

30–40 µg/levonorgestrel

1.9

1.5

2.4

 

non-fatal MI

 

 

35 µg/norgestimate

1.3

0.9

1.9

     

 

30 µg/desogestrel

2.0

1.5

2.7

     

 

20 µg/desogestrel

1.6

1.2

2.2

     

 

30 µg/gestodene

1.9

1.6

2.3

     

 

20 µg/gestodene

1.3

0.8

1.9

 

 

 

 

30 µg/drospirenone

1.7

1.0

2.7

3rd generation, CHC with desogestrel or gestodene; *Including also norgestimate; EE, ethinylestradiol

None of the progestogen only products conferred significantly increased risks of thrombotic stroke or of myocardial infarction.

 

Women at an increased risk of arterial thrombosis

Age is the most important risk factor of arterial thrombosis. In young women the baseline frequency of  thrombotic stroke and myocardial infarction is so low, that a 1.5–2 fold increased risk is not a major concern. In women past 35 years, on the other hand, no other risk factors for arterial thrombosis should be present. Smoking in particular confers a significant contribution to myocardial infarctions in women of reproductive age. Therefore smokers, especially heavy smokers, should not use CHC after 35 years. Women with diabetic vascular complications should also avoid CHC.

In young women below 35 years, several risk factors at the same time may also contraindicate use of CHC.

For women at an increased risk of arterial thrombosis, progestin only contraception may be a good alternative, because these products have not been found to increase the risk of neither thrombotic stroke nor myocardial infarction.

Previous thrombosis of any kind contraindicates CHC, but not necessarily progestin only products.

 

 

CONCLUSION

Besides an effective contraception, CHC offers several important non-contraceptive benefits, such as regular menstruation, diminished dysmenorrhea, less menstrual bleeding, and decreased risk of ovarian, endometrial and colorectal cancer. The thrombotic complications are the most important risk aspects. A large majority of women with VTE will survive their thrombosis, but a timely diagnosis and treatment is crucial for the prognosis. Therefore all efforts should be undertaken to ensure that women with contraindications against CHC are not prescribed such products, and that those who use these products are informed about the symptoms of especially VTE.

Previously, women with risk factors of thrombosis were told not to use any type of hormonal contraception. With newer large-scale studies, we now have sufficient scientific information to conclude, that progestin only contraception, such as levonorgestrel intrauterine system, progestin only pills, and implants do not significantly increase the risk of venous or arterial thrombosis, and that these products therefore, are not contraindicated for such women. Some of these products may even protect against VTE.

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