Effectiveness of Oral Contraceptive Pills in a Large U.S. Cohort Comparing Progestogen and Regimen

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Effectiveness of Oral Contraceptive Pills in a
Large U.S. Cohort Comparing Progestogen
and Regimen
Jürgen Dinger, MD, PhD, Thai Do Minh, PhD, Nina Buttmann, MD, MPH,
and Kristina Bardenheuer, MSc
OBJECTIVE: To estimate real-life effectiveness of oral
contraceptive pills by progestogen, length of pill-free
interval, and body mass index while focusing on the
effect of progestogens with a long half-life and on 24-day
oral contraceptive pills regimens.
METHODS: Outcome data from 52,218 U.S. participants
in the International Active Surveillance of Women Taking
Oral Contraceptives—a large, prospective, controlled,
noninterventional, long-term cohort study with active
surveillance of the study participants—were used to
analyze contraceptive failure in association with oral
contraceptive pills use. Low loss to follow-up is ensured
by a comprehensive follow-up procedure. Contraceptive
failure rates are described by Pearl Index and life-table
analysis. Inferential statistics for contraceptive failure are
based on Cox regression models.
RESULTS: Analyses are based on 1,634 unintended preg-
nancies during 73,269 woman-years of oral contraceptive
pills exposure. Life-table estimates of contraceptive failure
for a 24-day regimen of drospirenone and ethinyl estradiol
and 21-day regimens of other progestogens were 2.1% and
3.5% after the first study year, and 4.7% and 6.7% after the
third year. The adjusted hazard ratio was 0.7 (95% confi-
dence interval 0.6–0.8). Direct comparisons of the 24-day
and 21-day regimens of drospirenone and norethisterone,
respectively, showed also lower contraceptive failure rates
for 24-day regimens. Contraceptive failure rates adjusted
for age, parity and educational level showed a slight in-
crease with higher body mass index.
CONCLUSION: The 24-day oral contraceptive regimens
containing a progestogen with a long half-life show
higher contraceptive effectiveness under routine medical
conditions compared with conventional 21-day regi-
mens. Obesity seems to be associated with a slight
reduction of contraceptive effectiveness.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.
clinicaltrials.gov, NCT00335257.
(Obstet Gynecol 2011;117:33–40)
DOI: 10.1097/AOG.0b013e31820095a2
LEVEL OF EVIDENCE: II
Correct and consistent use of oral contraceptivepills is associated with unintended pregnancy
rates of as low as 0.3% during the first year. Under
“real-life” conditions of use, however, failure rates
have been found to approach 8%.1 Incorrect use, or
“missed pills,” is considered to be the main reason for
these higher failure rates over time.
An analysis of data from the European Active
Surveillance Study on Oral Contraceptives study found
low oral contraceptive failure rates (Pearl Index of 0.48).
which suggest a high level of correct use under real-life
conditions in the seven European countries involved.2,3
Data from the U.S. arm of the International Active
Surveillance of Women Taking Oral Contraceptives
study examined here come from a different population,
enabling comparisons, with respect to a potential rela-
tion between higher rates of extreme obesity and lower
contraceptive effectiveness.
Drospirenone is a progestogen with antiandro-
genic and antimineralocorticoid properties. A large
From the ZEG, Berlin Center for Epidemiology and Health Research, Berlin,
Germany.
Supported by an unconditional grant from Bayer Schering Pharma, Berlin.
The authors thank Marlene Schoofs for editorial support in preparing the
manuscript.
Corresponding author: Jürgen Dinger, ZEG, Berlin Center for Epidemiology and
Health Research, Invalidenstrasse 115, 10115 Berlin, Germany; e-mail:
dinger@zeg-berlin.de.
Financial Disclosure
Dr. Dinger consults with manufacturers of products discussed in this article and
received support for travel to the study’s Safety Monitoring and Advisory Council
Meetings from Bayer Schering Pharma. Ms. Bardenheuer received support for travel
to the study’s Safety Monitoring and Advisory Council Meetings from Bayer Schering
Pharma. The other authors did not disclose any potential conflicts of interest.
© 2010 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/10
VOL. 117, NO. 1, JANUARY 2011 OBSTETRICS & GYNECOLOGY 33
active postmarketing surveillance study has demon-
strated that a 21-day regimen of 3 mg drospirenone
and 30 microgram ethinyl estradiol (E2) can be used
safely for oral contraception.3 A 24-day regimen of 3
mg drospirenone/20 microgram ethinyl E2 (24 days
of active tablets followed by 4 days of inactive tablets)
was recently launched. The International Active Sur-
veillance of Women Taking Oral Contraceptives is
designed to investigate the safety and effectiveness of
this new regimen in a population that is representative
of typical oral contraceptive users. The International
Active Surveillance of Women Taking Oral Contra-
ceptives study is a “postauthorization safety study”
requested by the U.S. Food and Drug Administration
and the European Medicines Agency.
The 3 mg drospirenone/20 microgram ethinyl E2
regimen of 24 days of active tablets followed by 4
days of inactive tablets (drospirenone/ethinyl E224d)
may increase overall contraceptive efficacy. A recent
ovulation inhibition study investigated the effects of
“missed pills” (replacement of the first three pills with
placebo after a completed cycle) comparing a 24-day
and 21-day regimen of 3 mg drospirenone/20 micro-
gram ethinyl E2. Results showed that suppression of
ovarian activity, which resulted in decreased hor-
monal fluctuation, was substantially more pro-
nounced in the regimen of 24 days of active tablets
followed by 4 days of inactive tablets than the regi-
men of 21 days of active tablets followed by 7 days of
inactive tablets (drospirenone/ethinyl E221d).4–7
Therefore, it is conceivable that a progestogen with a
long half-life8 and a regimen that shortens the pill-free
interval, such as the 24-day regimen of 3 mg dro-
spirenone/20 microgram ethinyl E2, will further in-
crease contraceptive efficacy during “typical use.”
This article estimates real-life effectiveness of oral
contraceptive pills in the United States by progesto-
gen, length of pill-free interval, body mass index
(BMI, calculated as weight (kg)/[height (m)]2), and
other factors while focusing on the effect of progesto-
gens with a long half-life (such as drospirenone) and
on 24-day oral contraceptive pills regimens.
MATERIALS AND METHODS
The International Active Surveillance of Women
Taking Oral Contraceptives study is a large, prospec-
tive, controlled, noninterventional, long-term cohort
study with active surveillance performed in the
United States and several European countries. The
study is supervised by an independent Safety Moni-
toring and Advisory Council. In the United States,
approval from the Western Institutional Review
Board was received in July 2005. Participants in the
United States were enrolled between August 2005
and July 2008, whereas the European arm of the study
began recruitment in October 2008 as a result of later
market introduction in Europe. The main outcome of
interest is the occurrence of cardiovascular events (ie,
venous thromboembolism, myocardial infarction,
and cerebrovascular accidents). The secondary objec-
tive is the safety and effectiveness of drospirenone/
ethinyl E224d under real-life conditions. Sample size
has been calculated to sufficiently address both out-
comes. The study is powered (1���0.9; ��0.05) to
detect 0.8-fold contraceptive failure rate for dro-
spirenone/ethinyl E224d compared with otheroral
contraceptives and 0.6-fold contraceptive failure rate
for relevant subanalyses.
Recruitment into the study in the United States was
conducted via a network of 5,219 gynecologists in
private practice and clinics in all U.S. states representing
metropolitan as well as rural areas. Participating women
are new users of oral contraceptives, either first-time
users, recurrent users after a break in contraception or
users who have switched to a different type of pill.
Potential participants are informed of the noninterven-
tional study by their physicians only after the decision to
prescribe an oral contraceptive has been made, thereby
ensuring that the noninterference character of the study
is maintained. There are no specific medical inclusion or
exclusion criteria. Study participation is voluntary and
written informed consent is required. Information about
the potential study participation risks is provided in a
nondirective, standardized manner.
Baseline data on current state of health and
potential risk factors for oral contraceptive use are
obtained via a self-administered questionnaire. Partic-
ipants complete the baseline questionnaire at their
gynecologists’ offices, with the opportunity to clarify
questions with their gynecologists and the study
nurses. Subsequent follow-up questionnaires are
mailed to the participants biannually for up to 5 years
after baseline. The questionnaires collect information
on regular and continued oral contraceptive use and
the occurrence of pregnancy during oral contracep-
tive use. All women who report an unintended preg-
nancy while using their oral contraceptive are inter-
viewed in detail to assess potential reasons for oral
contraceptive failure, including whether any pills
might have been missed or incorrectly administered.
To prevent loss to follow-up, a comprehensive
four-level follow-up procedure is pursued. In the first
instance, up to two reminder letters are mailed to
women who do not return the follow-up question-
naire (level 1). In the absence of a completed ques-
tionnaire, multiple attempts are made to contact the
34 Dinger et al Real-Life Oral Contraceptive Pill Effectiveness OBSTETRICS & GYNECOLOGY
participants, their relatives, friends, and physicians via
phone (level 2), and searches in national and interna-
tional telephone and address directories were initiated
(level 3). Finally, level 4 activities include searches in
death registries and commercial address registries, as
well as official address search through governmental
administrations. The same procedure yielded in the
European Active Surveillance study3 a loss to fol-
low-up rate of 2.4%; interim results here indicate that
a similarly low loss to follow-up rate will be achieved
in the European arm of the International Active
Surveillance of Women Taking Oral Contraceptives
study. The final loss to follow-up in the United States
will be between 5% and 10%.
In agreement with current guidelines on the
clinical investigation of steroid contraceptives in
women that were published by the European Medi-
cines Agency,9 contraceptive failure rates are de-
scribed by Pearl Index and life-table analysis. Preg-
nancies were diagnosed by �-hCG measurements and
transvaginal ultrasonography. Calculation of contra-
ceptive failure in this study is based on all confirmed
unintended pregnancies that occurred while using an
oral contraceptive (numerator). The denominator is
the total oral contraceptive exposure during the same
time period. To calculate the Pearl Index in this study,
the number of pregnancies in the relevant cohort is
divided by the number of months of exposure in that
cohort, and then multiplied by 1,200. Ninety-five
percent confidence limits for Pearl Index are calcu-
lated using methods from Gerlinger.10
However, the comparison of exposures on the basis
of the Pearl Index might be misleading. For example,
the Pearl Index assumes a constant contraceptive failure
rate over time. That is an incorrect assumption, given
that contraceptive failure is more likely to occur in the
most fertile women and the women who use an oral
contraceptive for a long time are, on average, of lower
fertility (“attrition of susceptible”), and self-administered
contraceptive methods have better effectiveness in more
experienced users. Therefore, the presented analysis
focuses on life-table estimate methods (rate of contracep-
tive failure for each time interval, eg, months).
Predefined potential confounders were chosen
(age, BMI, smoking, parity, and education). This
selection accords the prognostic factors that were
included in the statistical model of the European
Active Surveillance study.2 Hazard ratios (HR) are
calculated for the variables age, BMI, smoking status,
parity, level of education, type of progestogen, and
oral contraceptive regimen.
Of special interest is the association between
contraceptive effectiveness and an oral contraceptive
regimen with a short pill-free interval that uses a
progestogen with long half-life and BMI. There have
been several studies suggesting lower oral contracep-
tive effectiveness with increasing BMI,11,12 and the
potential influence of obesity has triggered consider-
able discussion. The analysis of the European Active
Surveillance dataset mentioned showed a statistically
significant correlation between BMI and an increased
rate of contraceptive failure for only one of the five
progestogens in the study, with sufficiently large
sample sizes up to a BMI of 30. This U.S. arm of the
International Active Surveillance of Women Taking
Oral Contraceptives study seeks to find results for
higher BMI figures (35 or more). It therefore analyzes
and discusses BMI categories of less than 20.0, 20.0 to
24.9, 25.0 to 29.9, 30.0 to 34.9, and 35 or more.
Inferential statistics for contraceptive failure are based
on Cox regression models using the statistical soft-
ware packages StataES8 and SAS 9.
RESULTS
The presented analysis of this study is based on
52,218 U.S. women (64.9% non-Hispanic white
women, 14.9% Hispanic women, 14.3% non-Hispanic
African-American women, 2.2% Asian women, 1.2%
Native American women, and 2.5% other race or
ethnicity) who started use of a new oral contraceptive
after study entry and who signed informed consent
forms, yielding 99,382 woman-years of observation.
The corresponding loss to follow-up rate for these
U.S. women was 7.1%. The results on safety outcomes
and a detailed description of the baseline demo-
graphic characteristics of the study population are
reported separately. A summary of the prognostic
factors relevant for oral contraceptive effectiveness is
outlined and shown in Table 1. Analysis is performed
for three cohorts: drospirenone/ethinyl E224d, dro-
spirenone/ethinyl E221d, and oral contraceptive con-
taining other progestogens (“other oral contracep-
tives”). In addition, subanalysis of the other oral
contraceptives cohort included the 24-day and 21-day
regimens of oral contraceptives containing norethis-
terone acetate/ethinyl E2. Overall, the baseline de-
mographic characteristics were similar across cohorts.
A total of 10,032 women (19.2%) were oral contra-
ceptive starters (first ever users) and 42,186 women
(80.8%) were recurrent users. The mean age of study
participants is 26.3, with drospirenone/ethinyl E221d
users being slightly younger (25.7 years) compared
with users of drospirenone/ethinyl E224d (26.4 years)
and other oral contraceptives users (26.3 years). Mean
weight and mean BMI are similar across the three
cohorts. Mean BMI for the total study is 26.3 and as
VOL. 117, NO. 1, JANUARY 2011 Dinger et al Real-Life Oral Contraceptive Pill Effectiveness 35
follows for the three individual cohorts: 25.8 (dro-
spirenone/ethinyl E224d), 26.8 (drospirenone/ethinyl
E221d), and 26.4 (other oral contraceptives). Overall,
about 23.1% of the US study participants were obese.
At study entry, 43.5% of the U.S. study participants
were nulliparous, 16.5% were current smokers, and
29.5% had graduated from college.
Presentedanalyses of unintended pregnancies are
primarily based on “as treated” data, an approach that
accounts for product changes and shifts from oral
contraceptive use to no contraception. Analysis of
contraceptive failure is based on a total oral contra-
ceptive exposure of 73,269 woman-years. Overall,
1,634 unintended pregnancies have been reported, of
which 229 (14.0%) were reported for conditions of use
that gave no reason to indicate noncompliance de-
spite intensive questioning by investigators, and 1,405
(86.0%) were reported for conditions in which indica-
tions of noncompliant use were found. A comprehen-
sive analysis of potential reasons for contraceptive
failure showed that 46.3% of the women with unin-
tended pregnancies forgot to take the pill on time,
21.1% used antibiotics, and 9.5% reported an episode
of diarrhea or vomiting.
Contraceptive failure compared with age fol-
lowed a biphasic pattern; the highest rate of contra-
ceptive failure was observed in the 20- to 24-year
group, and a marked decline was observed in women
older than age 30 years (Fig. 1). Cox regression
analysis showed an HR of 0.2 (95% confidence inter-
val [CI] 0.2–0.3) for contraceptive failure in women
35 years and older compared with those younger than
35 years old.
Contraceptive failure rates adjusted for age, parity
and educational level showed a slight increase with
higher BMI (Fig. 2). An adjusted HR of 1.5 (95% CI
1.3–1.8) for contraceptive failure in women with a BMI
35 or more compared with less than 35 was found.
Parity and a low educational level were associated
with a higher contraceptive failure rate; the age-adjusted
0 
1 
2 
3 
4 
Less than 
20
20–24 25–29 30–34 35–39 40 or more
Age at event (years) 
C
on
tra
ce
pt
iv
e 
fa
ilu
re
 ra
te
 
(p
er
 1
00
 w
om
an
 y
ea
rs
)
Fig. 1. Oral contraceptive pill failure by age: point estimates
and 95% confidence intervals.
Dinger. Real-Life Oral Contraceptive Pill Effectiveness. Obstet
Gynecol 2011.
0
2
4
6
Less than 20.0 20.0–24.9 25.0–29.9 30.0–34.9 35.0 or greater
Body mass index (kg/m2)
C
on
tra
ce
pt
iv
e 
fa
ilu
re
 ra
te
(p
er
 1
00
 w
om
an
 y
ea
rs
)
Fig. 2. Oral contraceptive pill failure by body mass index:
point estimates and 95% confidence intervals.
Dinger. Real-Life Oral Contraceptive Pill Effectiveness. Obstet
Gynecol 2011.
Table 1. Baseline Characteristics of Study Participants
DRSP/EE24d DRSP/EE21d
Other OC
All NETA/EE24d NETA/EE21d
Users at study entry
(% of OC users)
10,302 (19.7) 3,982 (7.6) 37,935 (72.6) 10,332 (19.8) 2,543 (4.9)
Age (y) 26.4�7.4 25.7�6.5 26.3�7.1 27.0�7.7 26.5�7.5
Weight (kg) 70.0�17.4 72.9�19.9 71.5�18.4 70.3�17.5 69.6�17.4
BMI (kg/m2) 25.8�6.1 26.8�6.9 26.4�6.5 26.1�6.1 25.8�6.1
First-time users 2,140 (20.8) 668 (16.8) 7,224 (19.0) 2,306 (22.3) 487 (19.2)
Current smokers 1,544 (15.0) 719 (18.1) 6,362 (16.8) 1,714 (16.6) 441 (17.3)
Nulliparous women 5,247 (51.0) 2,082 (52.3) 15,363 (40.5) 3,752 (36.3) 1,163 (45.7)
College graduates 3,368 (32.7) 1,263 (31.7) 10,756 (28.4) 2,998 (29.0) 815 (32.0)
OC, oral contraceptive; DRSP, drospirenone; EE, ethinyl estradiol; 24 d, 24 days of active tablets followed by 4 days of inactive tablets;
21d, 21 days of active tablets followed by 7 days of inactive tablets; NETA, norethisterone acetate; BMI, body mass index.
Data are n (% of cohort) or mean�standard deviation unless otherwise specified.
36 Dinger et al Real-Life Oral Contraceptive Pill Effectiveness OBSTETRICS & GYNECOLOGY
HR for parous women was 2.5 (95% CI 2.3–2.8), and
women who graduated from college had an age-ad-
justed HR of 0.5 (95% CI 0.4–0.6). The crude HR for
current smoking was 1.4 (95% CI 1.2–1.6). However,
adjustment for age and educational level yielded a HR
of 1.1 (95% CI 1.0–1.3).
The overall Pearl Index calculated in this study is
2.2 (95% CI 2.1–2.3). The Pearl Index values for
drospirenone/ethinyl E224d, drospirenone/ethinyl
E221d, and other oral contraceptives are 1.6 (95% CI
1.4–1.9), 2.2 (95% CI 1.8–2.6), and 2.6 (2.4–2.7),
respectively.
Life-table estimates of the rate of contraceptive
failure ranged from 3.0% (95% CI 2.8–3.2) after the
first study year of oral contraceptive use to 6.2% (95%
CI 5.8–6.2) after the third study year. The corre-
sponding results for the three cohorts of interest
(Table 2 and Fig. 3) are 2.1% for drospirenone/ethinyl
E224d, 2.8% for drospirenone/ethinyl E221d, and 3.5%
for other oral contraceptives after the first year of oral
contraceptive use. Further subanalyses showed lower
life-table estimates of contraceptive failure rates (Fig.
4) for drospirenone/ethinyl E224d compared with no-
rethisterone/ethinyl E224d (2.1% and 3.5% after the
first year, respectively), as well as for drospirenone/
ethinyl E221d compared with norethisterone/ethinyl
E221d (2.8% and 4.7% after the first year, respectively).
This is also true for the direct comparison of the
24-day regimens of drospirenone and norethisterone
with the respective 21-day regimens.
Cox regression analysis that included age, BMI,
parity, smoking, and education as covariates yielded an
adjusted HR of 0.7 (95% CI 0.6–0.8) for drospirenone/
ethinyl E224d compared with 21-day regimens of other
progestogens. An intention-to-treat analysis yielded al-
most identical results (HR 0.7, 95% CI 0.6–0.8). Sensi-
tivity analyses using additional potential confounders
showed almost identical risk estimates. In addition,
direct comparisons of drospirenone/ethinyl E224d com-
pared with drospirenone/ethinyl E221d (HR 0.8), dro-
spirenone/ethinyl E224d compared with norethisterone/
ethinyl E224d (HR 0.7), drospirenone/ethinyl E221d
compared with norethisterone/ethinyl E221d (HR 0.7),
and norethisterone/ethinyl E224d compared with nore-
thisterone/ethinyl E221d (HR 0.8) showed statistically
significant lower HR for drospirenone or a 24-day
regimen or both. To consolidate these results, several
0.92
0.94
0.96
0.98
1.00
0 6 12 18 24 30 36
Duration of use (months)
P
ro
po
rti
on
 o
f n
on
pr
eg
na
nt
 o
ra
l c
on
tra
ce
pt
iv
e 
us
er
s
Drospirenone and ethinyl estradiol, 24-day regimen
Drospirenone and ethinyl estradiol, 21-day regimen
Other oral contraceptives
Fig. 3. Life-table estimates of contraceptive failure associ-
ated with the use of 24-day regimens of drospirenone and
ethinyl E2, 21-day regimens of drospirenone and ethinyl E2,
and other oral contraceptive pills.
Dinger. Real-Life Oral Contraceptive Pill Effectiveness. Obstet
Gynecol 2011.
0.88
0.91
0.94
0.97
1.00
P
ro
po
rti
on
 o
f n
on
pr
eg
na
nt
 
or
al
 c
on
tra
ce
pt
iv
e 
us
er
s
0 6 12 18 24 30 36
Duration of use (months)
Drospirenone and ethinyl estradiol, 24-day regimen
Drospirenone and ethinyl estradiol, 21-day regimen
Norethisterone acetate and ethinyl estradiol, 24-day regimen
Norethisterone acetate and ethinyl estradiol, 21-day regimen
 
Fig. 4. Life-table estimates of contraceptive failure. Com-
parison of two 24-day and two 21-day regimens of dro-
spirenone and ethinyl E2 (triangle) and norethisterone
acetate and ethinyl E2 (square), respectively.
Dinger. Real-Life Oral Contraceptive Pill Effectiveness. Obstet
Gynecol 2011.
Table 2. Life-Table Estimates of the Rate of
Contraceptive Failure After 1, 2, and 3
Years of Oral Contraceptive Use
Cohort
Contraceptive Failure (%) at
the End of Year
1 2 3
DRSP/EE24d 2.1 (1.7–2.4) 3.4 (2.9–4.0) 4.7 (3.8–5.6)
DRSP/EE21d 2.8 (2.2–3.3) 4.5 (3.6–5.4) 5.7 (4.5–6.9)
Other OC 3.5 (3.3–3.7) 5.4 (5.1–5.7) 6.7 (6.2–7.1)
DRSP, drospirenone; EE, ethinyl E2; OC, oral contraceptive.
Data presented as point estimates (95% confidence intervals).
VOL. 117, NO. 1, JANUARY 2011 Dinger et al Real-Life Oral Contraceptive Pill Effectiveness 37
stratified analyses of drospirenone/ethinyl E224d com-
pared with 21-day regimens of other progestogens were
performed (Table 3). Use of drospirenone/ethinyl E224d
was associated with a lower risk of contraceptive failure
for nulliparous and parous women, women who did and
did not graduate college,current smokers and nonsmok-
ers, women 25 years and older and women younger
than 25 years, as well as for women with a BMI of less
than 25 and 25 or more.
DISCUSSION
This study investigated contraceptive failure in a large
U.S. cohort of oral contraceptive users. A direct
comparison of our U.S. results with the European
based European Active Surveillance study3—a study
that used the same methodology—showed an approx-
imately four-fold higher contraceptive failure rate in
the United States, which confirms results from previ-
ous studies.13–15 Using strict criteria our results also
indicated noncompliant oral contraceptive use in 86%
of unintended pregnancies in the U.S. cohort. There-
fore, this study confirms that the very high pharma-
cological efficacy of oral contraceptives is substan-
tially reduced under real-life conditions in the United
States. However, improvement of compliance and
reduction of application errors (eg, by specific coun-
seling) could reduce U.S. contraceptive failure rates
substantially.
The study shows that contraceptive failure by
age follows a biphasic pattern (Fig. 1), which is in
line with findings that female fecundity peaks be-
tween 20 and 30 years of age,16 –18 and it is in line
with results from the European Active Surveillance
study.2 As expected, the study demonstrates that
parous women are more likely to become pregnant
during oral contraceptive use, independent of the
progestogen or regimen, than nulliparous wom-
en.19,20 Our results also indicate that a low educa-
tional level is a similarly strong prognostic factor
for contraceptive failure.
The European Active Surveillance study reported
low failure rates without a statistical significant asso-
ciation to obesity. However, it was not possible to
assess whether this nonassociation would also be seen
in populations with a higher proportion of women
with World Health Organization class II and class III
obesity (BMI 35 or more). A higher contraceptive
failure rate and higher prevalence of obesity in the
United States allowed us to analyze this question
using the International Active Surveillance of Women
Taking Oral Contraceptives data. We were able to
show a slight, but nevertheless statistically significant,
increase in contraceptive failure rates with increasing
BMI (Fig. 2). One possible explanation is that oral
contraceptives might be less forgiving of imperfect
use among obese women.21 Obesity might influence
the efficacy of oral contraceptives and women’s fer-
tility in opposite directions. For example, the high
distribution volume associated with class II and III
obesity may leads to lower drug concentrations and
subsequently may reduce ovarian suppression. How-
ever, obesity is associated with anovulation22 and it
may additionally influence sexual behavior. Our
study does not provide data that would allow estima-
tion of the effect of these factors. What matters in the
end is the sum of these factors, which translates into a
slight increase in the contraceptive failure rate. In
consideration of the rather low quantitative effect of
this effect, however, we feel that typical oral contra-
ceptives are adequately dosed for women who are
overweight or obese. Independent of this assessment,
prescribing physicians might consider progestin-only
or nonhormonal contraceptive methods for women
who are massively obese because combined oral
contraceptive use in these women is associated with a
substantially increased risk of cardiovascular side
effects.3
Absolute contraceptive failure rates are influ-
enced by several factors. The 2002 cycle of the U.S.
National Survey of Family Growth showed a contra-
ceptive failure rate of 7.7% during the first 12 months
of use.1 This is more than double the failure rate found
in our study. The major quantitative factors that could
explain this difference are the definition of person-
time in the denominator and differences in the study
population. In addition, the National Survey of Fam-
Table 3. Risk of Contraceptive Failure for a 24-
Day Regimen of Drospirenone/Ethinyl
Estradiol Compared With the 21-Day
Regimen of Other Progestogens,
Stratified by Prognostic Factors
Prognostic
Factor Stratum
Hazard
Ratio
95%
Confidence
Interval
Age (y) Younger than 25 0.7 0.6–0.8
25 or older 0.7 0.6–0.9
BMI (kg/m2) Less than 25 0.7 0.6–0.8
25 or more 0.7 0.6–0.9
College graduate No 0.7 0.6–0.8
Yes 0.6 0.4–0.8
Parity Nulliparous 0.7 0.6–0.9
Parous 0.7 0.6–0.8
Current smoker No 0.7 0.6–0.8
Yes 0.7 0.5–0.9
BMI, body mass index.
38 Dinger et al Real-Life Oral Contraceptive Pill Effectiveness OBSTETRICS & GYNECOLOGY
ily Growth methods differ from the International
Active Surveillance of Women Taking Oral Contra-
ceptives methods with regard to the frequency of data
collection and the definition of unintended preg-
nancy. Further methodological differences between
the International Active Surveillance/European Ac-
tive Surveillance and the National Survey of Family
Growth methodologies are discussed elsewhere.2
Because the International Active Surveillance of
Women Taking Oral Contraceptives study is obser-
vational, it is conceivable that our results are influ-
enced by residual confounding or bias, which never
can be entirely eliminated in this study design and
thus represents a limitation. The ability to infer cau-
sation or to exclude substance-specific risk therefore is
also limited.23 Although known potential confounders
were documented at baseline, adjustment cannot be
performed for unknown confounders. Education was
used as a proxy for socioeconomic status. It is con-
ceivable that this does not fully account for socioeco-
nomic differences between cohorts. Furthermore,
there may be selection bias associated with the readi-
ness to participate in a long-term study, although in
this case it is unlikely to have a differential effect on
the risk estimates.
Potential limitations of this study should not
detract from the strengths of the presented analysis.
First, International Active Surveillance of Women
Taking Oral Contraceptives is a large, prospective,
active cohort surveillance study. Because the study is
noninterventional in nature and specific inclusion and
exclusion criteria are not applied, participants are
probably representative of “typical” users of oral
contraceptives. The intensive follow-up procedure
pursued in International Active Surveillance of
Women Taking Oral Contraceptives yields a low rate
of loss to follow-up. It therefore may be assumed that
the study results are not biased by substantial under-
reporting of outcomes of interest and that the study is,
in general, methodologically valid.
The presented results on the differences between
drospirenone/ethinyl E224d, drospirenone/ethinyl
E221d, and other oral contraceptives are not unex-
pected. The long half-life of drospirenone (30 hours)8
combined with a 24-day regimen provides (partially)
suppressive progestogen levels even in the pill-free
interval. It is therefore plausible that a 24-day regimen
of drospirenone or any other progestin with a long
half-life yields better effectiveness than a 21-day reg-
imen of drospirenone or a 24-day regimen of a
progestogen with a short half-life under conditions of
imperfect use. The results were consistent across multi-
ple strata of relevant prognostic factors of contraceptive
failure and indicate that the pharmacokinetic proper-
ties of the progestogen and the short pill-free interval
contribute to the observed differences between dro-
spirenone/ethinyl E224d and conventional 21-day reg-
imens of other progestogens. Given the limitations of
observational research, the results of the International
Active Surveillance of Women Taking Oral Contracep-
tives study alone could not establish strong evidence of
the superiority of drospirenone/ethinyl E224d compared
with progestogens with shorter half-life or 21-day
regimens or both. However, taking the missed pill
study4 and the International Active Surveillance of
Women Taking Oral Contraceptives results to-gether, it is likely that the stronger ovarian suppres-
sion with drospirenone/ethinyl E224d translates to a
lower contraceptive failure rate under conditions of
typical oral contraceptive use.
REFERENCES
1. Kost K, Singh S, Vaughan B, Trussell J, Bankole A. Estimates
of contraceptive failure from the 2002 National Survey of
Family Growth. Contraception 2008;77:10–21.
2. Dinger JC, Cronin M, Möhner S, et al. Oral contraceptive
effectiveness according to body mass index, weight, age, and
other factors. Am J Obstet Gynecol 2009;201263.e1–9.
3. Dinger JC, Heinemann LA, Kühl-Habich D. The safety of a
drospirenone-containing oral contraceptive: final results from
the European Active Surveillance study on Oral Contracep-
tives (EURAS-OC) based on 142,475 women-years of obser-
vation. Contraception 2007;75:344–54.
4. Klipping C, Duijkers I, Trummer D, Marr J. Suppression of
ovarian activity with a drospirenone-containing oral contracep-
tive in a 24/4 regimen. Contraception 2008;78:16–25.
5. Spona J, Elstein M, Feichtinger W, Sullivan H, Lüdicke F,
Müller U, et al. Shorter pill-free interval in combined oral
contraceptives decreases follicular development. Contracep-
tion 1996;54:71–7.
6. Sullivan H, Furniss H, Spona J, Elstein M. Effect of 21-day and
24-day oral contraceptive regimens containing gestodene (60
microg) and ethinyl estradiol (15 microg) on ovarian activity.
Fertil Steril 1999;72:115–20.
7. Willis SA, Kuehl TJ, Spiekerman AM, Sulak PJ. Greater
inhibition of the pituitary–ovarian axis in oral contraceptive
regimens with a shortened hormone-free interval. Contracep-
tion 2006;74:100–3.
8. Krattenmacher R. Drospirenone: pharmacology and pharma-
cokinetics of a unique progestogen. Contraception 2000;62:
29–38.
9. European Medicines Agency Committee for Medicinal Prod-
ucts for Human Use. Guideline on clinical investigation of
steroid contraceptives in women, July 27, 2005. Available at:
http://www.emea.europa.eu/pdfs/human/ewp/ 051998en.pdf.
Retrieved April 14, 2010.
10. Gerlinger C, Endrikat J, van der Meulen EA, Dieben TO,
Düsterberg B. Recommendation for confidence interval and
sample size calculation for the Pearl Index. Eur J Contracept
Reprod Health Care 2003;8:87–92.
11. Brunner Huber LR, Hogue CJ. The association between body
weight, unintended pregnancy resulting in a livebirth, and
VOL. 117, NO. 1, JANUARY 2011 Dinger et al Real-Life Oral Contraceptive Pill Effectiveness 39
contraception at the time of conception. Matern Child Health
J 2005;9:413–20.
12. Holt VL, Scholes D, Wicklund KG, Cushing-Haugen KL,
Daling JR. Body mass index, weight, and oral contraceptive
failure risk. Obstet Gynecol 2005;105:46–52.
13. Darney P. Safety and efficacy of a triphasic oral contraceptive
containing desogestrel: results of three multicenter trials. Con-
traception 1993;48:323–37.
14. Ferguson H, Vree ML, Wilpshaar J, Eskes TK. Multicenter
study of the efficacy, cycle control and tolerability of a phasic
desogestrel-containing oral contraceptive. Eur J Contracept
Reprod Health Care 2000;5:35–45.
15. Grubb GS, Archer DF, Constantine GD. Differences between
the United States and Europe in clinical trials of hormonal
contraceptive efficacy. Obstet Gynecol 2008;111:63S.
16. Hamilton BE, Sutton PD, Ventura SJ. Revised birth and
fertility rates for the 1990s and new rates for Hispanic popu-
lations, 2000 and 2001: United States. Natl Vital Stat Rep
2003;51:1–94.
17. Larsen U, Yan S. The age pattern of fecundability: an analysis
of French Canadian and Hutterite birth histories. Soc Biol
2000;47:34–50.
18. Wood JW. Fecundity and natural fertility in humans. Oxf Rev
Reprod Biol 1989;11:61–109.
19. Trussell J. Methodological pitfalls in the analysis of contracep-
tive failure. Stat Med 1991;10:201–20.
20. Howe G, Westhoff C, Vessey M, Yeates D. Effects of age,
cigarette smoking, and other factors on fertility: findings in a
large prospective study. Br Med J (Clin Res Ed) 1985;290:
1697–700.
21. Trussell J, Schwarz EB, Guthrie K. Obesity and oral contra-
ceptive pill failure. Contraception 2009;79:334–8.
22. Friedman CI, Kim MH. Obesity and its effect on reproductive
function. Clin Obstet Gynecol 1985;28:645–63.
23. Susser M. What is a cause and how do we know one? A
grammar for pragmatic epidemiology. Am J Epidemiol 1991;
133:635–48.
40 Dinger et al Real-Life Oral Contraceptive Pill Effectiveness OBSTETRICS & GYNECOLOGY