CURRENT DEVELOPMENT

Modern oral contraceptives and cardiovascular disease

Lynn Rosenberg, ScD, a Julie R. Palmer, Sei)," Marti I. Sands, PhD, b David Grimes, MD, PhD, c
Ulf Bergman, MD, PhD, a Janet Daling, PhD, ¢ and Angela Mills, BM, BCh f
Boston, Massachusetts, Sau Francisco, California, Seattle, Washington, Stochholm, Sweden, and Lo~zdon,
United Kingdom

We reviewed evidence that bears on the cardiovascular safety of combined orai contraceptives
containing second- and third-generation progestogens and <50 i~g of estrogen. Recent epidemioiogic
studies indicate that current use of these formulations is associated with a smaller increase in the
incidence of venous thromboemboiism than eadier formulations. In some studies the increase for third-
generation formulations containing desogestrel or gestodene was about 1.5 to 2 times that for second-
generation formulations, hut there is evidence that differences between users in underlying risk and
iiketihood of being diagnosed contributed to th}s result. Recent studies of myocardial infarction suggest a
smaller increase in risk associated with modern formulations than with earlier ones; one study suggests a
threefold increase for second-generation formulations and no inorease for third-generation formulations,
but the finding requires confirmation. Recent studies of stroke indioate little or no increase in risk for
modern formulations among women without risk factors. We conclude that modern combined oral
contraceptives are safer than earlier formulations with respect to cardiovascuiar disease, which occurs
rarely in young women. (Am J Obstet Gynecol 1997;177:707-15.)

Key words: Oral contraceptives, cardiovascular disease

Epidemio~ogic studies established that il/st-generation
oral contraceptives--50 gg or more of estrogen com-
bined with a progestogen--increased the :cisk of venous
thromboembolism, stroke, and myocardial infarction. ~
Subsequent formulations have contained <50 ixg of
estrogen, and new progestogens have been developed,
such as levonorgestrel (second generation) and deso-
gestrel, gestodene, and norgestimate (third genera-
tion).2..~ Substantial epidemiologic evidence on the car-
diovascular safety of second- and third-generation oral
contraceptives has emerged only recently.
In October 1995 the British Committee on Safety of
Medicines, the equivalent of the U.S. Food and Drug
Administration, wrote to all physicians and pharmacists
in the United Kingdom about the safety of third-gener-
ation combined oral contraceptives. On the basis of the
resuhs of three then unpublished epidemiologic smd-
ies, .7 the committee warned that the risk of venous
thromboembolism among users of formulations contain-
ing desogestrel or gestodene was twice that among users
P~'om the Slone Epidemiology Unit, Boston Universily Schoo{ of Medi-
cine,~ the Sta*~ford Univ«rsi~y School of Medicine,z' the University of
CaliJbrnia, Sau Francisco, Medical SchooI,« the Ka:¢olinska Institute/«
the Fred Hutchinson Cancer Research Cente~; the University of Wash-
ing¢on,« and the United Elizabeth Ga~~ett Ander~on Hospital and
Hospital for Womenf
Supported in part by Organon, Inc., and Schering AG.
Reprint requests: Lynn Rosenberg, ScD, Slone Epidet~iology Unit, 1371
Beacon St., Broohline, MA 02146.
Copy~~ght © 1997 by Mosby-Year Booh, Inc.
0002-9378/97 $5.00 + 0 6/I/82739
of second-generation oral contraceptives; the studles
pro~dded no information on formulations containing
norgestimate. The committee recommended that oral
contraceptives containing desogestrel or gestodene be
used only by women who could not tolerate other
formulaüons. The advisory was followed by a pill scare, s
Many British women switched from third- to second-
generation oral contraceptives, others decided to use
alternative methods of contraception or n o n e at all,9 and
several months latera rise in u n p t a n n e d pregnancies and
an increase in abortions was observed, t°' 11
The studies on which the committee based its advisory
have now been published, as have several other smdies.
The findings are important to American women, health
professionals, and drug regulators. Third-generation oral
contraceptives containing desogestrel have captured
15% of the U.S. market, 1~ and second-generation formu-
!ations account for most of the remaining use. The recom-
mendations of the committee are controversial8, is I~: the
U.S. Food and Drug Administration has not affirmed the
recommendation, whereas Planned Parenthood has rec-
ommended that new users not receive oral contracep-
tives containing desogestrel. 16 This article reviews the
ex4dence beariug on the safety of low-estrogen second-
and third-generation oral comraceptives.
The evidence
The major epidemiologic findings on tirst-generation
orai contraceptives and cardiovascular disease were

707
708 R o s e n b e r 9 et al.
based on studies c o n d u c t e d mainly in the 1960s and
1970s/' 17 We briefly review those results and their bio-
logic plausibility, followed by a m o r e detailed review o f
data f r o m the r e c e n t studies of second- and third-
g e n e r a t i o n oral contraceptives.
Early studies
Epidemiologic evidence. Case-control and follow-up stud-
ies in the U n i t e d Stares and the U n i t e d K i n g d o m estab-
lished that there was an increased risk o f venous throm-
b o e m b o l i s m (deep vein thrombosis and p u l m o n a r y
embolism) in c n r r e n t users o f oral contraceptives. Risk
was u n r e l a t e d tO duration o f use and d e c l i n e d to the level
of nonusers within a m o n t h after cessation. ~' 17 Relative
risk estimates r a n g e d f r o m a b o u t 2 to 11. H i g h e r estro-
g e n doses were associated with a h i g h e r incidence, hut
no clear evidence linked the dose or type of p r o g e s t o g e n
to risk. 18-m
T h e risk o f myocardial infarction was increased three-
fold to fourfold in current users a n d it d e c l i n e d to
baseline within a m o n t h or so after cessation. L 17 Limited
evidence suggested that w o m e n who had used oral
contraceptives for long durations m i g h t be at increased
risk after cessation of use, z2 hut subsequent studies ruled
out that possibility. 23' 24 T h e increased risk in current
users was largely c o n f i n e d to cigarette smokers and older
women. 22 It was unclear w h e t h e r the estrogen c o n t e n t or
the dose or type of p r o g e s t o g e n affected the risk. 2°' 21
The incidence of thrombotic and hemorrhagic strokes
was incfeased a m o n g current oral contraceptive users, with
the Bfitish follow-up smdies indicating a relative risk of 5 for
stroke overall. ~' ~7 Equivocal evidence suggested that the
risk of hemorrhagic stroke might also be increased by past
use. 25 The strokes associated witb oral contraceptive use
were concentrated a m o n g smokers and older women.
Largely on the basis of British data, the i n c i d e n c e of
venous t h r o m b o e m b o l i s m per 100,000 w o m e n at risk p e r
year was estimated to be 110 for current oral contracep-
tive users and 30 for nonusers, with a case fatality rate of
1% to 2 % . 17'26-28 T h e c o r r e s p o n d i n g figures for the
i n c i d e n c e of myocardial infarction were l l for current
users and 4 for nonusers at ages 30 to 39 years and 89 for
c u r r e n t users and 22 for nonusers at ages 40 to 49 years,
with a case fatality rate of a b o u t 50%. 29 ~~ For stroke, the
estimates were 47 in users and 10 in nonusers, with a case
fatality rate of 5% to 10%. 17' 32.33
Pharmacologic effects and óioloßc mechanisms. Several
lines of evidence p o i n t e d to thrombosis as the likely
m e c h a n i s m by which oral contraceptive use increased
the risk. T h e e p i d e m i o l o g i c findings o f i n c r e a s e d risks of
venous t h r o m b o e m b o l i s m , myocardial infarction, and
stroke in c u r r e n t hut not past users suggested an acute
mechanism. Autopsy studies of w o m e n who died o f
myocardial infarction while using oral contraceptives
f o u n d evidence of clots. 34 Pharmacolog T studies indi-
cated that oral contracepfives increased the tendency for
September 1997
Am J Obstet Gynecol
both arterial and venous thrombosis, with some evidence
that the effects were related to the dose of estrogen.1
S o m e oral contraceptives had m a r k e d adverse effects
on carbohydrate and lipid metabolism, raising concern
about increased atherosclerosis. 21'35'3a T h e early oral
contraceptives with progestogens derived from 19-nor-
testosterone (e.g., norethisterone) t e n d e d to decrease
levels of high-density lipoprotein, increase levels of low-
density lipoprotein, and also impair glucose metabolism.
(Oral contraceptives with progestogens derived from
p r o g e s t e r o n e had little effect, bnt they were no l o n g e r
used after suspicion was raised that these progestogens
caused breast tumors in beagle dogs. 37' ss) However, the
e p i d e m i o l o g i c evidence weighs heavily against an athero-
sclerotic m e c h a n i s m insofar as past use and the duration
of use are largely u n r e l a t e d to risk.
Reeent studies
Epidemiologic evidence
VEyous THROMBOEMBOLISM
THE WORLD HEALTH ORGAN1ZATION COLLABORATIVE
STUDV. T h e World Health Organization (WHO) Collab-
orative Study is a hospital-based case-control study of
p r e m e n o p a u s a l w o m e n of childbearing ages c o n d u c t e d
d u r i n g 1989 t h r o u g h 1993 in 17 countries. 4 W o m e n with
first episodes of idiopathic venous t h r o m b o e m b o l i s m
were identified and interviewed in the h o s p i t a l - - 4 7 0
cases in E u r o p e and 747 in Africa, Asia, and Latin
America. For each case, up to three age-matched con-
trols were also interviewed, for a total of 2998.
T h e relative risk estimate for current oral contracep-
tive use relative to nonuse was increased about fourfold
in E u r o p e and threefold in the developing countries. 4
T h e major potential c o n f o u n d i n g variables considered,
hypertension, parity, obesity, and cigarette smoking, did
n o t materially influence the estimates.
Separate analyses of second- and third-generation oral
contraceptives were carried out. » Third-generation oral
contraceptives were nsed in nine countries, but most of the
use occurred a m o n g w o m e n from the Oxford center in the
United Kingdom. O n the basis of 158 cases and 360
hospital controls from Oxford, the relative risk estimate was
significantly elevated for use of third-generation oral con-
traceptives relative to nonuse (relative risk 6.8) and for use
of oral contraceptives containing levonorgestrel relative to
nonuse (relative risk 3.1) (Table I). Users of third-genera-
tion oral contraceptives containing norgestimate (one case
and two controls) were included with levonorgestrel users
becanse norgestimate is metabolized to levonorgestrel or its
metabolites.49, 43 For third-generation use compared with
levonorgestrel use, the relative risk estimate was 2.2 (95%
confidence interval 1.1 to 4.2). A m o n g users of desogestrel,
the relative risk estimate was greater for users of prepara-
tions containing 20 pg of ethinyl estradiol than of those
with 30 Ixg of ethinyl estradiol, but there were few users of
the former. Estimates in the other centers, on the basis of
Volume 177, Number 3 RoserlbeI'g et aIù 709
Am J Obstet GTmecol

T a b l e I, Resu]ts on venous t h r o m b o e m b o l i s m from r e c e n t studies

No. of cases per

Relative risk 100, 000 woman
estimate with 95 % years with 95%
Stuß, Comparison confidence interval co*~dence interval

Case-control studies
WHO~*
Oxford Third generation vs nonuse 48 6.8(3.5-13,4)
Levonorgestrelj" vs nonuse 40 3.1(1.7-5.5)
Third generation vs levonorgestrelt 2.2(1.1-4.2)
Other centers Third generation vs nonuse 23 20.7(7.9-53.7)
Levonorgestrel vs nonuse 97 4.0(2.7-5.8)
Third generation vs levonorgestrel 5.2(2.0-13.7)
Transnational 7
United Kingdom Third generation vs nonuse 98 4.4 (3.0-6.6)
Second generadont vs nonuse 64 3.0 (1.9-4.5)
Third generation vs second generationt 1.5 (1.0-2.2)
Germany Third generation vs nonuse 29 6.7 (3.4-13.0)
Second generationj- vs nonuse 88 3.7 (2.2-5.2)
Third generation vs second generationt 1.8 (1.0-3.3)
Transnational a9
United Kingdom and Norgestimate vs tevonorgestrel 19 1.85 (0.95-3.58)
Germany
Desogestrel with 30 Ixg estrogen vs 64 1.86 (1.23-2.83)
levonorgestrel
Desogestrel with 20 ixg estrogen vs 15 1.57 (0.80-3.07)
levonorgestrel
Gestodene vs levonorgestrel 58 !.68(1.10-2.56)
Leiden 4° Desogestrel vs nonuse 37 8.7(3.9-19.3)
Levonorgestrel vs nonuse 20 3.8(1.7-8.4)
Desogestrel vs le.vonorgestrel 2.2(0.9-5.4)
Follow-up smdies
General Practice Research Desogestrel 30 29.3 (20.5-41.9)
Database
Gestodene 22 28.1 (18.5-42.5)
Levonorgestrel 23 16.1 (10.7-24.3)
Meditel4t Second generation 29 31.0 (20.8-44.5)
Levonorgestrel 24 36.2 (23.2-53.8)
Second generation other than levonorgestreI 5 18.4 (6,0-42,9)
Third generation 54 49,6 (37.3-64.7)
Desogestrel plus 30 b~g esu-ogen 19 39.9 (24.0-62.2)
Desogestrel plus 20 txg estrogen 13 115.3 (61.4-197.1)
Gestodene 22 44.1 (27.5-68.8)
*Results based on hospital controls.
j'Includes norgestimate.

smaller numbers and with wider confidence intervals, sug-
gested a similar pattern to that observed in the United
Kingdom.
TRANSNATIONAL STUDY. The Transnational Study, 7, 44
f u n d e d by the m a n u f a c t u r e r of oral contraceptives con-
taining gestodene, was c o n d u c t e d d u r i n g 1993 t h r o u g h
1995 in the U n i t e d Kingdom, Germany, and three o t h e r
E u r o p e a n countries with m e t h o d s similar to those used
in the W H O study. T h e study was halted after publication
of the W H O results.
O n the basis o f 983 cases o f v e n o u s t h r o m b o e m b o l i s m
from the U n i t e d Kingdom, the relative risk estimate was
significantly elevated, 4.4-fold, for c u r r e n t use of third-
g e n e r a t i o n oral contraceptives containing g e s t o d e n e or
desogestrel and threefold for use of second-generation
oral contraceptives, relative to n o n u s e (Table I). For
comparability with the W H O analysis, 5 oral contracep-
tives containing norgestimate (18 cases and 28 comrols)
were i n c l u d e d with second-generation oral contracep-
tives. In a c o m p a r i s o n of third-generation with second-
g e n e r a t i o n oral contraceptives, the relative risk estimate
was 1.5 (95% c o n f i d e n c e intervat 1.0 to 2.2). Allowance
was m a d e for age, alcohol use, cigarette smoking, study
center, body mass index, and the duration of oral
contraceptive use. Results f r o m G e r m a n y »vere h i g h e r
but showed a similar pattern. Results o b t a i n e d separately
with hospital and c o m m u n i t y controls were similar.
In a further analysis, 39 i n d M d u a i f o r m u l a ü o n s were
c o m p a r e d separately with oral contraceptives containing
levonorgestrel; in these comparisons, users of norgesti-
mate were no l o n g e r i n c l u d e d with levonorgestrel. T h e
relative risk esdmate, ranging from 1.57 to 1.86, was in-
creased for every third-generation oral c0ntraceptive for-
mulation, including preparations containing norgestimate
710 R o s e n b e r g et at.
(Table I). It was also elevated for second-generation oral
contraceptives containing progestagens other than
levonorgestrel, 1.56, and for first-generation oral contracep-
tives, 1.94. In a subanalysis conducted among women aged
25 to 44 years, the relative risk was greater the more recently
the formulation had been introduced (p < 0.001 for
trend). Relative to oral contraceptives containing levonorg-
estrel, which were first marketed in early 1970s, the relative
risk estinaate increased from 1.46 for oral contraceptives
containing desogestrel and 30 b~g of estrogen, marketed in
1981, to 2.84 for oral contraceptives containing desogestrel
and 20 I~g of estrogen, introduced in 1988 in the United
Kingdom and in 1992 in Germany.
GENERAL PRACTICE RESEARCH DATABASE. The General
Practice Research Database contains computerized clinical
records from general practices in the United Kingdom.6 In
a study ofidiopathic nonfatal venous thromboembolism, 80
women with evidence of treannent with anticoagulants and
admission to the hospital were identified. The incidence of
venous thromboembolism per 100,00Õ woman years at risk
was estimated to be 16.1 for levonorgestrel users, 29.3 for
desogestrel users, and 28.1 for gestodene users (Table I). In
a nested case-control smdy carried out within this study, in
which calendar year, smoking status, and body mass index
»vere eontrolled together with two broad categories of age,
the relative risk estimates for desogestrel use and for
gestodene use relative to levonorgestrel use were both
elevated twofold.
MEDITEL STUDIES. The Meditel Studies used a comput-
erized database derived from general practice records. In
one study 116 cases of venous thromboembolism with
evidence of specific treatment (e.g., anticoagulants) or
admission to the hospital with the diagnosis of pulmo-
nary embolism were identified. 45 The incidence of ve-
nous thromboembolism per 100,000 woman years at risk
was estimated to be 11.4 in nonusers of oral contracep-
tives, 30.5 in users of combined oral contraceptives
containing 30 to 35 t*g of estrogen, 30.3 in users of
progestogen-only oral contraceptives, and 59.1 in preg-
naht women. In a further report on formulation-specific
risks, 46 the incidence of venous thromboembolism per
100,000 woman years at risk was estimated to be 34.6 for
women who used a formulation containing desogestrel
(Marvelon); that estimate did not differ significantly
from estimates for formulations containing levonor-
gestrel (Microgynon, Ovranette, Logynon) or gestodene
(Femodene), but numbers were small.
In a subsequent study based on 83 cases of venous
thromboembolism,41 the incidence of venous thrombo-
embolism was about 60% greater in users of third-
generation progestogens relative to second-generation
progestogens, and the highest incidence was observed
for users of desogestrel plus 20 Ixg of ethinyl estradiol
(Table I). In a nested case-control study that controlled
for exact year of age and several other confounding
September 1997
B n J Obstet Gynecol
factors, the relative risk for the comparison of deso-
gestrel plus 20 ~xg of ethinyl estradiol to second-genera-
tion oral contraceptives was 3.49 (95% confidence inter-
val 1.21 to 10.12), and the estinaate for other third-
generation formulations was 1.18 (95% confidence
interval 0.66 to 2.17).
LEIDEN THROMBOPHILIA STUDY. The Leiden Throm-
bophilia Smdy was a population-based stndy of first
episodes of venous thrombosis conducted during 1988
through 1992 in the Netherlands. 4° Lach case identified
a friend or acquaintance, or the partner of another case
was chosen, matched on sex and age to the case. Earlier
findings from this study were that factor V Leiden
mutation was present in 6% of control women and that
the risk of venous thrombosis among carriers was in-
creased eightfold overall and thirtyfold among carriers
who were receiving oral contraceptives. 47
Analysis of specific formulations, prompted by the results
of the WHO study, 5 was based on 126 female cases and 159
female controls.4° For current oral contraceptive use rela-
tive to nonuse, the age-adjusted relative risk for formula-
tions containing 30 b~g of ethinyl estradiol together with
desogestrel was 8.7; for formulations that contained
levonorgestrel, lynestrenol, or norethisterone, the estimates
ranged from 2.2 to 3.8. A comparison of desogestrel-
containing formulations with levonorgestrel-containingfor-
mulaUons that both contained 30 I*g of ethinyl estradiol
yielded a relative risk of 2.2 (Table I). Adjustment for family
history, factor V Leiden mutation, or history of pregnancy
did not change the relative risk estimates.
OTHER STUDIES. Several earlier studies provided data
on second-generation oral contraceptives hut bad no
information on third-generation oral contraceptives. 4s-52
Most suggest that the risk of venous thromboembolism is
lower for oral contraceptives containing lower doses of
estrogen.
MYOCARDIAL INFARCTION
TRANSNAT1ONAL STUDY. The Transnational Study of
myocardial infarction compared 153 wonnen with first
myocardial infarctions, of whom 129 were from the
United Kingdom or Germany, with 210 hospital and 288
commnnity controls) 3 The methods were the same as
those in the study of venous thromboembolism.7 With
control for the duration of oral contraceptive use and
cigarette smoking, the relative risk estimate for current
use of third-generation oral contraceptives containing
desogestrel or gestodene relative to nonuse was close to
1.0; for second-generation oral contraceptives relative to
nonuse, the relative risk was significantly elevated, 3.1
(Table II). For the comparison of third-generation to
second-generation use, the relative risk estimate was 0.36
(not statisticaIly significant). In an updated report based on
a larger sample, 5~ the relative risk estimate for third-gener-
ation users (7 cases) versus second-generation users (28
cases) was 0.3 (95% confidence interval 0.1 to 1.0).
Volume 177, Number 3 Rosenberg et aI. 711
Am J Obstet Gyneco[

T a b l e II. Results o n myocardial i n f a r c t i o n a n d stroke f r o m r e c e n t studies

Exposed
8(~$8S Relative rish estimate and
Study Outcome (No.) 95 % co~~fide~ceimerva!

Transnational »3 Myocardial Third generaüon vs nonuse 6 1.1 (0.4-3.4)

infarction
Se«ond generation* vs nonuse 2.3 3.1 (L>ö.:~)
Third generation vs second generation* 0..% (o.t4.2)
WHO (Europe) 54t Ischemic Se«ond and third generations vs nonuse 20 1.53 (0.71-3.31)
stroke
Second generation vs nonuse 16 L53 (0.694.s9)
Third generation vs nonuse 4 1.76 (0.33-9.36)
WHO (Europe) 55~r Hemorrhagic Second and third generations vs nonuse 27 x._97 (0.70-2.3s)
stroke
Third generation vs second generation No significant difference;
data not given

*lncludes norgestimate.
kFormulations with <50 b~g of estrogen.

o w a s n STErnES. I n a study o f m y o c a r d i a l i n f a r c t i o n
b a s e d o n t h e G e n e r a l Practice R e s e a r c h Database, 57 the
relative risk estimates for t h e c o m p a r i s o n of c u r r e n t use
of oral c o n t r a c e p t i v e s c o n t a i n i n g desogestrel or gesto-
d e n e to use of oral c o n t r a c e p t i v e s with levoF orgestrel did
n o t differ significantty, b u t t h e n u m b e r of users was ve U
small. A r e c e n t U.S. p o p u l a t i o n - b a s e d case-controi study
of myocardial i n f a r c t i o n 5s f o u n d t h a t c u r r e n t use o f oral
c o n t r a c e p t i v e s c o n t a i n i n g < 5 0 Ixg o f e s t r o g e n was re-
lated to a smaller i n c r e a s e in risk t h a n h i g h e r dose
f o r m u l a t i o n s - - r e l a t i v e risk 1.65 a n d n o t statistically sig-
nificant. T h e r e was n o i n f o r m a t i o n o n the relative effects
o f second- a n d t h i r d - g e n e r a t i o n formula'.ions. Earlier
studies 59-(s~ also s u g g e s t e d a lower risk for f o r m u l a t i o n s
with lower doses o f estrogen.
STROKE
WHO COLLAgORATIVE STUDY. T h e ~ ~ I O Collaborative
Study assessed i s c h e m i c stroke (697 cases, 1962 controls)
in its h o s p i t a l - b a s e d study o f cardiovascular disease. ~4
T h e overall relative risk for c u r r e n t oral c o n t r a c e p t i o n
users was i n c r e a s e d a b o u t t h r e e f o l d b o t h in E u r o p e a n d
in t h e d e v e l o p i n g countries, b u t estimates were lower for
y o n n g e r w o m e n a n d for f o r m u l a t i o n s with lower doses o f
estrogen. I n E u r o p e t h e relative risk estimate for c n r r e n t
use of f o r m u l a t i o n s with < 5 0 ixg o f e s t r o g e n was 1.54 a n d
n o t statistically significant; t h e estimates were similar for
second- a n d t h i r d - g e n e r a t i o n progestogens: b u t n u m b e r s
were small (Table II). T h e risk was i n ¢ r e a s e d a b o u t
fivefold or m o r e for w o m e n w h o b o t h s m o k e d a n d u s e d
oral c o n t r a c e p t i v e s a n d m o r e t h a n t e n f b l d t o r users w h o
gave a history of h y p e r t e n s i o n .
T h e ~2-IO Collaborative S m @ also assessed h e m o r -
rhagic stroke (1068 cases, 2910 controls), intracerebral
h e m o n - h a g e (420 cases, 1173 controls), a n d s u b a r a c h n o i d
h e m o r r h a g e (608 cases, 1644 controls).55 T h e overall rela-
tive risk for h e m o r r h a g i c stroke was < 2 in boch E u r o p e a n d
the developing countries, a n d the esümate for Europe,
1.38. was n o t staUsticatly significant (Table II) Relative risk
esdmates were lower for y o u n g e r women. Risk was consid-
erably increased a m o n g users who smoked, a b o u t three-
fold, a n d a m o n g users with hypermnsion, m o r e than ten-
fold. Results for intracerebral a n d s u b m a e h n o i d h e m o r -
rhage were similar. It was r e p o r t e d that t h e r e were n o
significant differences according to the type of progestogen
used. b u t n o data were shown.
OTHER STUDIES. A U,S, p o p u l a ü o n - b a s e d case-control
studv of strokes o c c m r i n g d u r i n g 3,8 million w o m e n -
years o f o b s e r v a t i o n f o u n d n o i n c r e a s e in risk o f ischemic
stroke a m o n g c u r r e n t users o f oral c o n t r a c e p t i v e s , rela-
tive risk 1.18). ~~ For h e m o r r h a g i c s~roke t h e overall
relative risk esumate was also d o s e to 1.0. b u t there was a
suggestion of an m t e r a c u o n to mcrease the risk bv a b o u t
3.5-fold a m o n g smokers. Virtualtv all oral eomraceptive use
was of low estrogen dose ( < 5 0 btg) preparations. T h e r e was
n o i n f o r m a t i o n o n the relative safety of second- and rhird-
g e n e r a t i o n fornmlafions. A n eartier s m @ of stroke also
suggested a lower risk of su-oke for users of lower estrogen
dose oral contracepuve preparations. ~:~
Pharmacologic effects and biologic mech.anisms. In an at-
m m p t to r e d u c e adverse effects, oral c o n t r a c e p t i v e m a n -
ufacturers have lowered e s t r o g e n doses to a b o u t o n e fitih
o f t h e i r original c o n t e n t a n d have r e d u c e d p r o g e s t o g e n
doses a b o u t tenfold. "%64 T h e search for new p r o g e s m -
g e n s has f o c u s e d o n d e v e l o p i n g c o m p o u n d s t h a t are less
a n d r o g e m c a n d t h a t have liU.le or n o m~pact o n lipid
m e t a b o l i s m o r glucose tolerance. I n d e e d . clinical studies
i n d i c a t e t h a t e a c h g e n e r a u o n o f c o m b i n e d oral contra-
ceptives h a s h a d smaller effects o n lipid m e t a b o t i s m a n d
glucose t o l e r a n c e t h a n t h e p r e v t o u s generation/~~v~~a
Second- a n d t h i r d - g e n e r a t i o n oral c o n t r a c e p u v e s have
small effects on t h e h e m o s t a u c system. :< (s4.~»5 T h e y ~end
to increase the t e n d e n c y to c o a g u l a t i o n , b u t they also
increase fibrinolvsis. Effects o n t h e n a m r a l a m i c o a g u l a -
tion system vary, b u t t h e g e n e r a l t e n d e n c v is to a reduc-
712 Rosenberg et al.
tion in factors that inhibit coagulation. Even after the
changes, values of the hemostatic variables rend to be
within normal ranges. These effects appear to be related
to the estrogen dose and are smaller than those of older
oral contraceptives that had higher doses of estrogen. It
is not known how the changes relate to clinical events.
In a pharmacokinetics study of 22 women published in
198967 serum levels of ethinyl estradiol were considerably
higher in gestodene users than in desogestrel users. Be-
cause adverse outcomes such as hypertension and venous
thromboembolism have been related to the estrogen con-
tent, the results raised the concern that oral contraceptives
with gestodene might carry a greater risk. The German
regulatory authorities issued an alert, which was followed by
the initiation of the Transnational Study. Subsequent stud-
ies have not detected differences in serum levels of ethinyl
estradiol between women using gestodene- and desogestrel-
containing oral contracepdves. 68-7s
Comment
The recent e~idence on myocardial infarction and
stroke indicates that second- and third-generation oral
contraceptives are safer than first-generation formula-
tions. Formulations with <50 txg of estrogen had little or
no influence on the risk of stroke in women without risk
factors.54, »5, 02 One study of myocardial infarction sug-
gests an increase in risk associated with second-genera-
tion formulations and no increase for third-generation
pills,53,56 but the latter finding requires confirmation.
There is no obvious biologic rationale for third-genera-
tion formulations to affect the risk of myocardial infarc-
tion less than second-generation pills do. Mthough third-
generation formulations are associated with fewer
adverse effects on lipid profiles, the epidemiologic data
suggest that oral contraceptives affect risk through
thrombosis rather than through atherosclerosis.
With regard to venous thromboembolism, relative risk
estimates in recent studies 4-7'39-41,45.46 have been similar
to or smaller than those for first-generation pills, and the
underlying incidence of venous thromboembolism was
lower than in the early studies 5 (see below). Thus mod-
ern pills appear to cause fewer cases of venous thrombo-
embolism than earlier formulations did.
Some studies suggest that third-genera6on oral contra-
ceptives are associated with an increase in the risk ofvenous
thromboembolism about 1.5-fold to twofold greater than
that associated with second-generation formulations. Does
the evidence support a causal explanation?
There is no convincing evidence that third-generation
oral contraceptives containing gestodene or desogestrel
affect hemostasis or other biologic systems in a way that
would increase the risk of thrombosis relative to other
formulations.», 64, 65 Not is there convincing evidence for
a greater increase in risk associated with desogestrel
formulations containing 20 fxg of estrogen than those
September 1997
AmJ Obstet Gynecol
containing 30 Ixg of estrogen, as has been observed in
several studies. 5' 39, 41 In addition, the relative risk esti-
mates for the comparison of third- to second-generation
oral contraceptive users have been of a magnitude that
might well be explained by biases. Thus it is necessary to
assess whether there is evidence of biases that may have
influenced the findings.
Problems with diagnosis are inherent in any smdy of
venous thromboembolism. The condition manifests with
a variety of symptoms and may resolve spontaneously.
Oral contraceptive users who have certain symptoms,
such as swelling in the leg, may be more often referred
and more rigorously worked up for venous thromboem-
bolism than nonusers are. 74'7» This would lead to a
tendency to overestimate the incidence ofvenous throm-
boembolism for oral contraceptive users relative to non-
users and also to overestimate the risk attributable to oral
contraceptive use. The results based on the German data
in the Transnational Smdy are compatible with this bias:
The relative risk estimates were higher than those based
on the United Kingdom data, possibly because of earlier
widespread media coverage in Germany of a smdy that
suggested adverse pharmacokinetics of oral contracep-
tives containing gestodene. 67
If the diagnosis had been related to the specific oral
contraceptive formulation used, comparisons between
formulations could also have been biased. A survey of
physicians in Germany, 75 conducted after the issuance of
the advisory of the United Kingdom Committee on
Safety of Medicines, suggested that they had been more
likely to investigate the symptoms ofwomen perceived to
be at higher risk, because of obesity or family history of
thrombosis, for example. The physicians also reported
that they were more likely to prescribe third-generation
oral contraceptives to such women. Thus third-genera-
tion users may have had a higher likelihood of referral
for investigation of symptoms of thrombosis.
The comparison between second- and third-genera-
tion oral contraceptive use would have been biased in all
of the studies if users of second- and third-generation
oral contraceptives differed in their susceptibility to
venous thromboembolism. Such a difference could have
occurred by two mechanisms. Orte involves the depletion
of susceptible women from the pool of users. Women
who have a genetic susceptibility to venous thromboem-
bolism, such as those positive for factor V Leiden muta-
tion, may have venous thromboembolism soon after
starting oral contraceptive use and they will be removed
from the pool of users. More susceptible women may
have been removed from among users of a formulation
long on the market than from among users of a newer
formulation. Another mechanism is differential prescrib-
ing. If particular oral contraceptives are perceived as
being safer (third-generation oral contraceptives were
promoted as being safer), women thought to be at
 Volume 177, Number 3
Am J Obstet Gynecol
greater risk of venous t h r o m b o e m b o l i s m may be selec-
tively given those formulations.
Evidence for a greater attrition of susceptible w o m e n
from a m o n g users of oral contraceptives longer on the
market is found in the Transnational Smdy. In the analysis
of individual formulations relative to formulations with
levonorgestrel, which was on the market longest, 39 the
relative risk estimate for oral contraceptives containing
norgestimate was elevated, and similar in magnimde, to
that for desogestrel and gestodene. Because norgesümate is
converted in part to levonorgestrel and to its metabo-
lites,42, 43 there is no compelling biologic credibility for a
difference in risk between formulafions with levonorgestrel
and norgesümate. In addition, a m o n g womela aged 25 to
44 years, the magnitude of the relative risk estimate was
greater the more recently the formulation had been mar-
keted, a p a t t e r n consistent with greater attrition of w o m e n
susceptible to venous thromboembolisn~ a m o n g users of
formulaüons that were in use longer. In accord with this,
relative risk estimates in the W H O Smdy 5 and the most
recent Meditel Study 41 were gweater for w o m e n who used
desogestrel ~4th 20 b~g of ethinyl estradiol than for those
who used this progestagen »~4th 30 g g of ethinyl estradiol.
The duration of use of third-generation oral conU'aceptives
was shorter than that of second-generation oral contracep-
tives,7 which is also compatible with ditferent!:al attrition of
susceptible women.
Evidence suggestive of differential prescribing is found in
surveys of prescribers. Surveys of British, 76 German, 75, 76
and French 7v physicians indicated a tendency to prescribe
third-generation formulaUons for w o m e n at higher risk.
Similar results have also been reported for Dutch prescrib-
ers. 7s If this vype of preferential prescribing had operated in
the recent epidemiologic studies, the resultt would have
been an upward blas in the relative risk esüma m cornparing
third- with second-generation oral contraceptive users.
In summmT, there is evidence of biases ',hat may have
c o n t r i b u t e d to the apparently greater risk of venous
thrornboembolisnt in third-generation users c o m p a r e d
with second-generation users.
Risks and benefits of second- and third-
generation oral contraceptives
Cardio~~scular disease rarely occurs in young women.
O n the basis of data from the Oxford c o m p o n e n t of the
V~~tO study, the incidence of idiopathic venous thrombo-
embolism per 100,000 woman years at risk was estimated to
be 3.9 for nonusers, 10.5 for users of oral contracept/ives
containing tevonorgestrel, 21.3 for users of formulations
containing desogestrel or gestodene, and 1:2.3 for ttsers of
other oral contraceptives, r' Esfimates based on the Meditel
database 45 were higher (e.g., 50% greater fi»r users of oral
contraceptives with levonorgestrel), but both the W H O and
Meditel estimates are an order o f m a g n i t u d e lower than the
estimates from epidemiologic studies cor~ducted in the
Rosenberg et al. 713
1960s and 1970s. 1 Some of the differences between the early
and recent estimates ma,,/be explained by more precise
diagnosis of venous thromboembolism in the recent smd-
ies. Whatever the explanation, the data suggest that the
incidence of venous thromboembolism attributable to use
of m o d e r n oral contraceptives is less than that associamd
with first-generation fbrmnlations. The incidence ofvenous
thromboembolism in pregnant w o m e n has been esUmated
to be about 60 per 100,000. 45 Thus use of second- or
third-generation oral contraceptives can-ies less risk of
venous thromboembolism than pregnancy does. The inci-
dence of stroke per 100,000 w o m e n per year, based on
European data in the ~~~IO Smdy, was estimated to be 4.8
for nonusers and 6.7 for users of lower estrogen dose oral
contraceptives; in a U.S. smdy the overall incidence was
about 11 per [00,000 w o m e n per year, and it diltkred little
according to oral contracepüve use. The incidence of
myocardial infarction estimated from a recent U.S. smdy
was about 5 per 100,000 woman years) ~
With regard to mortality, deaths from myocardial
infarction a m o n g w o m e n < 4 5 years old e x c e e d those
f r o m venous t h r o m b o e r n b o l i s m and stroke. ~, ~4, 7~/Thus
the relative safety of second- and third-generation oral
contraceptives ~qth reference to mortality d e p e n d s on
their effect on mortality f r o m myocardial infarction. T h e
Transnational Study resutts suggest that third-generation
oral contraceptives are safer than s e c o n d - g e n e r a d o n
formulations in terms of the i n c i d e n c e of myocardial
infarction, but they require c o n f i r m a t i o n Y T h e r e are no
informative data available on mortality.
Aside f l o m the prevendon of pregnancy and its atten-
dant risks, oral contraceptives containmg >.50 b~g of estro-
gen had several unanticipated benefits, the most i m p o n a n t
being reductions in the incidence of ovarian and endome-
trial cancer. An anMysis based on data from the Oxford
Famity Planning Association follow-up studv of oral comra-
ceptive users and nonusers indicated that the benefits m
decreased morbidit3, and mortality ounveighed the m-
creased risks associated with use. ~° The benefit-risk equa-
üon for second- and third-generauon oral contracepdves is
not established but. as already noted, there is evidence that
these formulations are safer v,4th respect ~o cardiovascular
disease than earlier oral contraceptives were.
We thank Drs. Daniel Cramer, William Brown. Sonia
Buist, Fritz Kernper. and Walter Spi~er for their commenLs.
REFERENCES
1. Stadel BV. Oral contracepuves and cardiovascular disease.
N EnglJ Med 1981:305:612-7. 672-7.
2. Robinson GE Low-dose combined orat contraceptives. BrJ
Obstet Gynaecol 1994;101:1036-41.
3. Newton JR. Classification and comparison of oral contracep-
tives containing new generauon progestogens. Hure Re-
prod Update 1995:1:231-63.
a,. Poulter NR. Chang CL, Farlev TMM. Meirik O. Mavmot MG
Venous thromboembolic disease and combined oral contra-
714 R o s e n b e r g et al.
ceptives: results of international multicenter case-control
study, World Health Organization Collaborative Study of
Cardiovascutar Disease and Steroid Hormone Contracep-
tion. Lancet 1995;346:1575-82.
5. Farley TMM, Meirik O, Chang CL, Marmot MG, Poulter NR.
Effect of different progestagens in low oestrogen oral con-
traceptives on venous thromboembolic disease. Lancet 1995;
346:1582-8.
6. tick H, Jick SS, Gurewich V, Myers IVI~7, Vasilakis C. Risk of
idiopathic cardiovascular death and nonfatal venous throm-
boembolism in women using oral contraceptives with differ-
ing progestagen components. Lancet 1995;346:1589-93.
7. Spitzer WO, Lewis MA, Heinemann LAJ, Thorogood M,
MacRae KD. Transnational Research Group on Oval Con-
traceptives and the Health of Young Women. Third gener-
ation oval contraceptives and risk of venous thrombolic
disorders: an international case-control study. BMJ 1996;312:
83-8.
8. Anonymous. Pill scares and public responsibility [editorial].
Lancet 1996;347:1707.
9. Graham A, Grieve F, DavieJ, Glasier A. Oral contraceptives
and venous thromboembolism [letter]. Lancet 1995;346:
1430.
10. British Pregnancy Adviso~T Service. Number of abortions;
comparison over 3 months: December-FebruatT 1993/94 to
1995/96. West Midlands (UK): The Service; 1996.
11. Huge rise in abortions after government's warning: human
cost of the pill scare. Daily Mail 1996 Apr 15.
12. Food and Drug Adminisu'ation. Oral contraceptives and risk
of blood clots. FDA Talk Paper 1995 Nov 14.
13. Johannisson E, International Committee for Research in
Reproduction. Safety of modern oval contraceptives. Lancet
1996;347:258.
14. MacRae K, Kay C. Third generation oral contraceptive pills:
is the scare over the increased risk of thrombosis justified?
BMJ 1995;311:1112.
15. McPherson K. Third generation oral contraception and
venous thromboembolism: the published evidence confirms
the Committee on Safety of Medicine's concerns. BMJ
1996:312:68-9.
16. Planned Parenthood Federation of America. Update:
thromboembolic impact of oval contraceptives. New York:
Planned Parenthood Federation of America; 1996.
17. ¥essey MP. Female hormones and vascular disease: epide-
miologic overview. B r J Farn Plann 1980;6(suppl):l-12.
18. Oval contraceptives, venous thrombosis, and varicose veins:
Royal College of General Practitioners' Oval Contraception
Smdy. J R Coll Gen Pract 1978;28:393-9.
19. Stolley PD, Tonascia JA, Tockman MS, Sartwell PE, Rut-
ledge AH, Jacobs MP. Thrombosis and low-estrogen oral
conu-aceptives. Am J Epidemiol 1975;102:197-208.
20. Inman WHW, Vessey MP, Westerholm B, Engelund A.
Thromboembolic diseases and the steroidal content of oval
contraceptives: a report to the Committee on Safety of
Drugs. BMJ 1970;2:203-9.
21. Meade TW, Greenberg G, Thompson SG. Progestogens and
cardiovascular reactious associated with oral contraceptives
and a comparison of the safety of 50- and 30-pùg oestrogen
preparations. BIVIJ 1980;280:1157-61.
22. Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen
OS, Stolley PD. Risk of myocardial infarction in relation to
current and discontinued use of oral contraceptives. N Engl
J Med 1981;305:420-4.
23. Rosenberg L, PalmerJR, Lesko SM, Shapiro S. Oral contra-
ceptive use and the risk of myocardial infarction. Am J
Epidemiol 1990;131:1009-16.
24. Stampfer MJ, Willett WC, Colditz CA, Speizer FE, Hennek-
ens CH. A prospective study of past use of oral contraceptive
agents and risk of cardiovascular disease. N Engl J Med
1988;319:1313-7.
25. Petitti DB, Wingerd J. Use of oral contraceptives, cigarette
smoking, and risk of subarachnoid haemorrhage. Lancet
1978;2:234-5.
September 1997
Am J Obstet Gynecol
26. Mortaliß among oral-contraceptive users: Royal College of
General Practitioners' Oral Contraception Study. Lancet
1977;2:72%31.
27. Vessey MP. Steroid contraception, venous thromboembo-
lism, and stroke: data from countries other than the United
States. In: Sciarra JJ, Zamchni GI, Speidel JJ, editors. Risks,
benefits, and controversies in fertility control. Hagerstown
(MD): Harper & Row; 1978. p. 113-21.
28. Maguire MG, TonasciaJ, Sartwell PE, Stolley PD, Tockman
MS. lncreased risk of thrombosis due to oral contraceptives:
a further report. Am J Epidemiol 1979;110:188-95.
29. Mann JI, Vessey MP, Thorogood M, Doll R. Myocardial
infarction in young women with special reference to oral
contraceptive practice. BMJ 1975;2:241-5.
30. Mann JI, Inman WHW. Oral contraceptives and death from
myocardial infarction. BMJ 1975;2:245-8.
31. Mann JI, lnman WHW, Thorogood M. Oval contraceptive
use in older women and fatal myocardial infarction. BMJ
1976;2:445-7.
32. Royal College of General Practitioners. Oval contraceptives
and health. London: Pitman; 1974.
33. Vessey MP, McPherson K, Yeates D. Mortality in oval con-
traceptive users. Lancet 1981;1:549-50.
34. Engel HJ, Engel E, Lichtlen PR. Coronary atherosclerosis
and myocardial infarction in young women--role of oral
contraceptives. Eur Heart J 1983;4:1-8.
35. Wynn V, Adams PW, Godsland I, Melrose J, Niththyanan-
than R, Oakley NW, et al. Comparison of effects of different
combined oral contraceptive formulations on carbohydrate
and lipid metabolism. Lancet 1979;1:1045-9.
36. Tikkanen MJ, Nikkila EA. Oval contraceptives and lipopro-
rein metabolism. J Reprod Med 1986;31 (suppl):898-905.
37. Weisz J, Ross GT, Stolley PD. Report of the public board of
inquiry on Depo-Provera. Rockville (MD): U.S. Food and
Drug Administration, 1984.
38. World Health Organization. Facts about injectable contra-
ceptives: memorandum from a WHO meeting. Bull WHO
1982:199-210.
39. Lewis MA, Heinemann LAJ, Mac Rae Kl), Bruppacher R,
Spitzer WO, Transnational Research Group on Oral Con-
traceptives and the Health of Young Women. The increased
risk ofvenous thrombolism and the use of third generaUon
progestagens: role of bias in observational research. Contra-
ception 1996;54:5-13.
40. Bloemenkamp K'V\~I, Rosendaal FR, Hehnerhorst FM,
Buller HR, Vandenbroucke JP. Enhancement of factor V
Leiden mutation of risk of deep-vein thrombosis associated
with oral contraceptives containing third-generation proge-
stagen. Lancet 1995;346:1593-6.
41. Farmer RDT, Lawrenson RA, Thompson CR, KennedyJG,
Hambleton IR. Population-based study of risk of various
thromboembolism associated with various oral contracep-
tives. Lancet 1997;349:83-8.
42. Stanczyk FZ, Roy S. Metabolism of levonorgestrel, noreth-
indrone and structurally related contraceptive steroids.
Contraception 1990;42:67-96.
43. Shenfield GM, Griffin JM. Clinical pharmacokinetics of
contracepfive steroids: an update. Clin Pharmacokinet
1991;20:15-37.
44. Spitzer WO, Thorogood M, Heinemann L. Trinatioual
case-control study of oval contraceptives and health. Phar-
macoepidemiol Drug Saf 1993;2:21-31.
45. Farmer RDT, Preston TD. The risk of venous thromboem-
bolism associated with low oestrogen oral contracepfives. J
Obstet Gynaecol 1995;15:195-200.
46. Farmer R. Safety of modern oral contraceptives [letter].
Lancet 1996;347:259.
47. Vandenbroucke JP, Koster T, Brier E, Reitsma PH, Bertina
RM, Rosendaal FR. Increased risk of venous thrombosis in
oral contraceptive users who are carriers of factor V Leiden
mutation. Lancet 1994;344:1453-7.
48. Böttiger LE, Boman G, Eklund G, Westerholm B. Oral
Volume 177, Number 3
Am J Obstet Gynecol
contraceptives and thromboembolic disease: eßects of low-
ering oestrogen content. Lancet 1980;1:1097-101.
49. Vessey M, Mant D, Smith A, Yeates D. Oral contraceptives
and venous thromboembolism: findings in a large prospec-
üve study. BMJ 1986;292:526.
50, Helmrich SP, Rosenberg L, K~ufman DW, Strom B, 8hapiro
S. Venous thromboembolism and oral contraeeptive use.
Obstet Gynecol 1987;69:91-5.
51. Gerstman BB, Piper JM, Tomita DK, Ferguson \~~, Stadel
BV, Lundin FE. Oral contracepuve estrogen dose and the
risk of deep venous thromboembolic disease. Am J Epide-
miol 1991;133:32-7.
52. Thorogood M, Mann J, Murphy M, Vessey M. Risk factors
for fatal venous thromboembolism in young women: a
case-control study. I n t J Epidemiol 1992;21:48-52.
53. Lewis MA, Spitzer WO, Heinemann LAJ, MacRae KI),
Bruppacher R, Thorogood M, et al. Third generation oral
com.raceptives and risk of myocardial infarction: an inter-
national case-control study. BMJ 1996;312:88-90.
54. Poulter NR, Chang CL, Farley TM, Meirik O, Marmor MG,
lschaemic stroke and combined oral contraceptive: results
of an international, multicentre, case-control study, V(HO
Collaborative Study of Cardiovascular Disease and 8teroid
Hormone ConFacepfion. Laneet 1996;348:498-505.
55. Poulter NR, Chang CL, Farley TM, Meirik O, Marmot MG.
Haemorrhagic stroke, overall stroke risk, and combined
orai contraceptives: results of an international, multicentre,
case-control smdy, W-HO Collaborative 8tudy of Cardiovas-
cular Disease and Steroid Hormone Contraception. Lancet
1996;348:505-10.
56. Lewis MA, Heinemann LAJ, Spitzer WO, Bruppacher R,
Thorogood M, MacRae Kl). Results of the Transidonal
Case-Control Study on Oral Contraceptives. Proceedings of
the Twelflh International Conference on Pharmacoepide-
miology; 1996 Aug 28; Amsterdam, Amsterdam: Interna-
üonal Conference on Pharmaeoepidemiolo~~; 1996,
57. Jick H, Jick SS, Meyers NI~~, Vasilakis C, Risk of acute
myocardial infarction and ]ow-dose combined oral contra-
ceptives [letter]. Lancet 1996;347:627-8.
58. Sidney S, Petitti DB, ~uesenberry CPJr, Klatsky AL, Wolf S.
Myocardial infarction in users of low dose oral contracep-
tives. Obstet Gynecol 1996;88:939-44.
59. Adam SA, Thorogood M, Mann JI, Oral contracepfion and
myocardial infarction revisited: the effects of new prepara-
tions and preseribing patterns. Br J Obstet Gynaecol 1981;
88:838-45.
60. Thorogood M, Mann J, Murphy M, Vessey M. Is oral
contraceptive use still associated with an increased risk of
fatal myocardial infarction? B r J Obstet G>~aecol 1991;98:
1245-53.
61. Rosenberg L, Palmer JR, Lesko SM, Shapiro S. Oral contra-
ceptive use and the risk of myocardial infarction. Am J
Epidemiol 1990;131:1009-16.
62. Petitti DB, Sidney S, Bernstein A, Wolf S, Queensber U C,
Ziel HK. Stroke in users of Iow-dose orai contraceptives.
N Engl J Med 1996;335:8-15.
63. Lidegaard O. Oral contraception and r[sk of cerebral
thromboembolic attack: results of a case-control study. BMJ
1993;306:956-63.
64, Fotherby K, Caldwell ADS. New progestogens in oral con-
traception. Contraception 1994;49:1-32.
65. Speroff L, De Cherney A, Advisory Board for the New
R o s e n b e r g et ai. 715
Progestins. Evaluation of a new generation of orai cont~-a-
ceptives. Obstet Gynecol 1993;81:1034-47.
66. Godsland IF, Crook D, Simpson R, Proudler T, Felton C,
Lees B, et al. TEe etfect of different formulations of oral
contraceptives on lipid and carbohydram metabolism.
N Engt ] Med 1990;323:1375-81.
67. Jung-Hoffmann C, Kuhl H. Interaction wilh the pharmaco-
kinetics of ethinyl estradiol and progestogens contained in
oral contraceptives. Contraception 1989;40:299-312.
68. Himpel M, Tauber U, Kuhnz W, Pfeffer M, Brill K, Hein
becker R, et al. Comparison of serum ethinyl es~radiol,
sex-hormone-binding globulin, corticoid-binding globu!in
and corüsol levels in women using two low-dose combined
oral contraceptives. Horm Res 1990;33:35-9.
69. Kuhnz W. Pharmacokinetics of the contraceptive ste,roids
levonorgestrel and gestodene after single and multiple oral
administraüon to women. ~Mn J Obstet Gynecol 1990;163:
2120-7.
70. Kuhnz W, Sostarek D, Gansau C, Louton T, Mahler M.
Single and muttiple administration of a new triphasic oral
contraceptive to women: pharmacokinetics of ethinyl estra-
diol and free and total testosterone levels in serum. Am J
Obstet Gynecol 1991;165:596-602.
71. Back DJ, Ward S, Orme MLE. Recent pharmacokenkic
studies of low-dose oraI contraceptives. Adv Contracept
1991;7(supp1 3):164-79.
72. Dibbel~ L. Knuppen R. Jütting G, Heinmann S, Klipping
CO. Parikka-Olexik H. Group comparison of serum ethinvl
estradiol. SHBG and CBG levels in 83 women usmg rwo
low-dose combination oral contraceptives for/hree months
Contracepdon 1991:43:1-21.
73. Orme M. Back DJ, Ward S, Green S. The pharmacokinedcs
of ethynylestradiol in the presence and absence ot gesto-
dene and desoges:rel. Contracepdon 1991;43:305-16.
74. ReMini JP, Goldzieher JW. Oral conu'aceptives and cardio-
vascular disease: a criuque of epidemiologic studies. Am J
Obstet G',necol 1985:152:729-98.
75. Heinemann LAJ, Lmds MA. Assmann A. Cravens L. Guggen-
moos-Hoizmmm I. Conld preferential prescribing and referral
behavior of phvsicians explain the elevated thrombotic risk
ibund ro be associated with third generation ora] contracep-
tives? Pharmacoepidemiol Drug Saf 1996:5:285-94.
76. Dunn N. Heinemann LAJ, Mann RD. Are tbird-generation
oral contraceptives reallv more /hrombotic than second-
generation: some potential biases examined and compared
in German and English doctors. Proceedings of the Twelfth
International Conference on Pharmacoepidemiology; 1996
Aug 28; Amsterdam. Amsterdam: International Co~fference
on PharmacoepidemiologT; 1996.
77. Jamin C. de Mouzon J. Selective prescribing of third-
generation oral contraceptives (OCs Contraception 1996:
54:55-6.
78. Herings RIVlC, de Boer A. Urquliart J, Leufkens HGM.
Non-cansal explanations for the increased dsk of venous
thrombembo]ism among users of third-generation oral con-
traceptives. Pharmacoepidemiol Drng Saf 1996;5:588.
79. Faculty of Famih' Planning and Reproductive Health. State-
ment from the Clinicai and Scientific Committee: risk of
venous thromboembolism and the combined oral con~ra-
ceptive pill. London: The Faculty; 1995.
80. Vessev MP. Benefits and risks of combined oval conu'acep-
tives. Meth Inform Med 1993;32:222-4.