Neurology

Thrombotic Stroke and MyocardialInfarction with Hormonal Contraception

nejm.org june 14, 2012
د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

The rates of thrombotic stroke and myocardial

infarction increased by factors of 20 and 100, respectively, with increasing age. Only small differences in risk were observed between women who took combination pills containing intermediatedose
ethinyl estradiol (30 to 40 μg) and those who
took low-dose ethinyl estradiol (20 μg), and only
minor variations in risk were associated with different
progestin types.


The increased incidence of thrombotic stroke
over the 15-year study period probably reflects
improvements in the diagnostic equipment, allowing
the detection of small cerebral infarctions,
rather than a real increase in incidence. The steep
increase in incidence with older age has been
shown in several previous studies. This information has clinical implications, given that arterial thrombosis after the age of 30 years is more frequent and has more serious consequences than venous thrombosis.

The risk of arterial thrombosis should therefore be considered together with the risk of venous thrombosis when hormonal contraception is prescribed.
The relative risk of thrombotic stroke of 1.4 to
2.2 among current users of oral contraceptives
containing ethinyl estradiol at a dose of 30 to
40 μg is slightly lower than previously reported.

In a multicenter World Health Organization study,

Poulter et al. found that women who used second generation oral contraceptive pills with levonorgestrel,
as compared with nonusers, had a relative
risk of thrombotic stroke of 2.7 (95% CI, 1.8 to
4.1) and users of third-generation pills had a relative
risk of 1.8 (95% CI, 0.6 to 5.2).


Among women who had their blood pressure measured before obtaining a prescription, these risk estimates were reduced to 2.0 (95% CI, 1.1 to 3.6) and 1.6 (95% CI, 0.4 to 6.6), respectively.9 These estimates are closer to ours, perhaps because a majority of Danish women have their blood pressure
checked before obtaining prescriptions for oral
contraceptives.

In our secondary analysis, which included only

the code for cerebral infarction, we observed a
slightly higher relative risk of stroke associated
with hormonal contraception, as compared with
our primary analysis. This difference may have
been due to the inclusion of 15 to 20% of hemorrhagic strokes in the primary analysis that were coded as cerebral apoplexy, supporting the finding that oral contraception is associated with a
lower risk of cerebral hemorrhage than of cerebral
infarction.

Heinemann et al. reported a case–control study

showing that women who used second-generation
oral contraceptive pills with levonorgestrel or norgestimate had a risk of thrombotic stroke that was
2.7 times (95% CI, 1.5 to 4.6) as high as the risk
among nonusers and those who used third-generation
pills had a risk that was 3.4 times (95% CI,
1.9 to 6.4) as high.10 These estimates are higher
than those reported in the present study.


In a previous Danish case–control study that covered the period from 1994 through 1998, we found that users of second-generation oral contraceptive pills had a risk of cerebral thromboembolism that was 2.2 times (95% CI, 1.6 to 3.0) as high as the risk among nonusers.11 The odds ratio for cerebral thromboembolism among users
of third-generation pills was 1.4 (95% CI, 1.0 to 1.9).

These results are in accordance with our current findings.

Gronich et al. recently found that oral contraceptives
with drospirenone and ethinyl estradiol at
a dose of 30 μg were associated with the same
magnitude of risk as second-generation and thirdgeneration pills with the same dose of estrogen
— results that are in agreement with ours. Our
data suggest a relatively high risk of thrombotic
stroke with the use of a vaginal ring and possibly
with the use of transdermal patches.

Until further evidence emerges, one might expect a higher risk of thrombotic stroke with parenteral administration than with oral administration (estrogen combined with progestin).
There was a relatively high correlation in risk
estimates for thrombotic stroke and myocardial
infarction among the different product groups
a finding that increases the likelihood that the
observed differences in risk were real rather than
random variations.


One previous study showed atendency toward a higher relative risk of myocardial infarction with the use of third-generation, as compared with second-generation, oral contraceptives,
16 three showed the opposite result, and one showed no difference18 (Table 4S in the Supplementary Appendix). We found no consistent difference according to progestin type, but the risk decreased with lower doses of estrogen. We also found that low-dose pills were associated with approximately a 50% increase in the risk of myocardial infarction and intermediate-dose pills with
up to a 100% increase in risk.

A crucial point in all registry-based studies is

the validity of the diagnostic codes. In our 2002
study, we excluded 5.0% of women with a diagnosis
of thrombotic stroke because of an absence
of confirmation from the patient or the treating
department. The diagnosis of myocardial infarction
has been found to be valid in 93.6% of patients
of all ages,29 and the percentage is probably
higher among young patients.

Any diagnostic misclassification may have led to an underestimation of the relative risks among current users. Another limitation is that, for some women, there may have been a time lag between the date of the prescription and the date the medication was actually
started.

We had detailed and valid exposure information

because the prescriptions were transferred electronically
from the pharmacies by bar codes linked to the personal identification number.
We were thus free of recall bias, an issue of concern
in all retrospective case–control studies. The national
cohort design ensured a large sample and
allowed the calculation of risk estimates for specific
product groups according to estrogen dose,
progestin type, and route of administration — the
majority with an acceptable precision. The design
also avoided the problem of sample reduction
due to nonresponse in survey studies, ensuring a
high external validity.


For the levonorgestrel-releasing IUD, we had
information only about the dates that the women
received the IUD. Although this IUD has a valid
period of 5 years, many women have it removed
before the expiration date. Because of this uncertainty,
we censored data for women with a
levonorgestrel-releasing IUD after 3 years, unless
another prescription for hormonal contraception
was filled before that date. This approach reduced
our exposure time for this specific product but
increased the probability that the women who
were classified as having a levonorgestrel-releasing
IUD actually did have it.

Data on body-mass index were not available, but

body-mass index was not a confounder in our
previous study. Smoking, although an important
risk factor for arterial thrombosis, had no confounding
influence in either this study or our
previous one, in which we had more comprehensive
information about this potential confounder.
Therefore, it is not likely that our results were
strongly influenced by incomplete data on these
two potential confounders.


However, in the absence of definitive data, we cannot be sure whether there would be an interaction with smoking.
In conclusion, women who used oral contraceptives
with ethinyl estradiol at a dose of 30 to
40 μg had a risk of arterial thrombosis that was
1.3 to 2.3 times as high as the risk among nonusers,
and women who used pills with ethinyl
estradiol at a dose of 20 μg had a risk that was
0.9 to 1.7 times as high, with only small differences
according to progestin type.

We estimate that among 10,000 women who use desogestrel with ethinyl estradiol at a dose of 20 μg for 1 year, 2 will have arterial thrombosis and 6.8 women taking the same product will have venous thrombosis.
Although venous thrombosis is three to four
times as frequent as arterial thrombosis among
young women, the latter is associated with higher
mortality and more serious consequences for the
survivors. Therefore, these figures should be taken
into account when prescribing hormonal contraception.