Emergency Contraception

Joseph B. Stanford, MD, MSPH

University of Utah
Department of Family and Preventive
Medicine
April 2008
This talk
 What is emergency contraception?
 How effective is EC?
 How does EC work?
 What should patients be told about EC?
 The FDA approval process for OTC status
of ‘Plan B’
 What will be the public health effects of
OTC status of ‘Plan B’?
Disclosures
 I have never received funding from a
pharmaceutical company related to EC.
 I have scientific and ethical concerns
about EC.
 I believe in honest, balanced research and
information for patients.
What is emergency
contraception?
What is emergency contraception?

 Contraception after intercourse

 Yuzpe regimen “Preven”
 Ethinyl estradiol 100 g + levonorgestrel 500 g x2 (12 hrs)
 Levonorgestrel 0.75 mg x2 (12 hrs) or 1.5 mg x1
 “Plan B”
 Mifepristone 10 mg (RU-486)
 Copper IUD
 Others in development
What is emergency contraception?

 Contraception after intercourse

 Yuzpe regimen “Preven”
 Ethinyl estradiol 100 g + levonorgestrel 500 g x2 (12 hrs)
 Levonorgestrel 0.75 mg x2 (12 hrs) or 1.5 mg x1
 “Plan B”
 Mifepristone 10 mg (RU-486)
 Copper IUD
 Others in development
History of EC

 Yuzpe regimen “Preven”

 First proposed in 1974
 =4 pills of most combined oral contraceptives x2 (12 hrs)
 “Preven” approved by FDA 1998 as prescription;
taken off market August 2004
 Levonorgestrel 0.75 mg x2 (12 hrs) or 1.5 mg x1
 =20 pills of progestin-only contraception x1
 “Plan B” approved by FDA 1999 as prescription
 OTC application 2003, approved August 24, 2006
 Mifepristone 10 mg
 Not yet FDA approved (no time soon)
How long after?

 FDA: within 72 hours

 Advocates: within 120 hours, but more
effective with earlier administration, so
take as soon as possible.
 Rationale for OTC or advanced
prescription.
How effective is EC?
Perfect use and typical use
pregnancy rates- EC

 Perfect use
 Excludes anyone with additional intercourse
after EC use, not completing dose, etc.
 Typical use
 All users, all kinds of use
Perfect use and typical use
pregnancy rates- EC

 WHO 1998 (n=997)

 Randomized trial of Yuzpe vs. Plan B
 Perfect use 89% (product promotion)
 Typical use 85%
 NOT based on randomization!
 Basedon external comparison of expected
pregnancies in historical group
Randomized trials of EC
 Unethical to randomize women to placebo
 Comparison has been another regimen of
EC
 Most often Yuzpe regimen
How is effectiveness calculated?

 (E-O)/E = 1- O/E = effectiveness (%)

 E= expected pregnancies
 O=observed pregnancies
WHO 1998

Levonorgestrel Yuzpe

Typical Perfect Typical Perfect

N 997 574 1001 583
O. 11 5 31 11
Preg
E. 73.3 45.5 72.0 45.8
Preg
Eff. 85% 89% 57% 76%
WHO 1998
 RR LNG/Yuzpe = 0.36 (0.18-0.70)
 Unknown how effective Yuzpe is, or even
whether it is effective at all!
 Day-specific probabilities of
conception from 2 studies (Dunson et al)

0.45
0.4
0.35
0.3
0.25 Barrett/Marshall
0.2 Wilcox et al
0.15
0.1
0.05
0
-5 -4 -3 -2 -1 0

Human Reproduction 1999;14:1835-1839.

http://humrep.oupjournals.org/cgi/content/full/14/7/
1835
Problem in calculating Expected
pregnancies
 EC studies do not have marker for day of
ovulation
 Usual solution for EC studies: count
backwards from end of cycle 14 days and
then use probabilities for 6-day window up
to and including ovulation
Problem in calculating Expected
pregnancies
 EC studies do not have marker for day of
ovulation
 Count backwards from end of cycle 14
days and then use probabilities for 6-day
window
 Wrong solution!
 Ignores normal variation in length of luteal
phase (9-18 days)
 Different approaches to
calculate expected pregnancies
 Dixon- adjusts for previous cycle length
 Trussell- adjusts for previous cycle length
(most often used in EC studies)
 Wilcox- adjusts for luteal length
 Mikolajczyk and Stanford- adjusts for
previous cycle length and luteal length
simultaneously
Biases of different approaches

Mikolajczyk and Stanford, Fertil Steril 2005

Biases of different approaches
 Depends on window of presentation
 Studies take women presenting early in cycle
 Therefore bias with most approaches in most
studies is to overestimate EC effectiveness
How effective is Plan B really?

90
80
70
60
50
Plan B
40
30
20
Plan B Effectiveness
10
0
0 25 50 75
Yuzpe Effectiveness

Raymond et al, Contraception 2004

How effective is Plan B really?
 72% typical use
 Under assumptions of minimal selection bias
 May be less than this

 Compare to 89% (7/8) claims for perfect use in

package insert and promotional ads

Stanford and Mikolajczyk, Curr Rev Wom Health 2006

How does EC work?
Early Human Development

 Fertilization usually occurs in outer third

of fallopian tube.
 Prevent fertilization = contraceptive effect
 The early embryo implants in the uterus
5-14 days later.
 Prevent development after fertilization,
implantation, or development after
implantation but before clinically recognized
pregnancy = postfertilization effect
How does EC work?
 Before fertilization
 Prevent ovulation
 (Prevent sperm migration)

 After fertilization?
 Prevent implantation
 Biologic evidence mixed for LNG

 Some human studies show endometrial effects

 Animal studies show no effect after fertilization

Human follicular ultrasound

Follicular 12-14mm 15-17mm =>18mm

diameter
No rupture 83% 36% 12%

Ovulation 94% 91% 47%

Disturbed

Croxatto, Contraception 2004

Human follicular ultrasound

Follicular 12-14mm 15-17mm =>18mm

diameter
No rupture 83% 36% 12%

Ovulation 94% 91% 47%

Disturbed
Probability Very low Moderate High
Conception

Croxatto, Contraception 2004

How does EC work?
 Epidemiologic approach
 Combine probability of ovulation
disturbance with probability of conception
 Fecund window=6 days
 Delay of administration
 As time between intercourse and administration
of EC increases, so does the probability that
conception (fertilization) has occurred before
EC was given.
Plan B effectiveness and mechanism
(Based on ovulation and ultrasound data)

With 72, 48, 24, and 0 hours’ delay in administration

Mikolajczyk and Stanford, Fertil Steril 2007
Plan B effectiveness and mechanism
(With theoretical maximum prefertilization effects)

With 72, 48, 24, and 0 hours’ delay in administration

Mikolajczyk and Stanford, Fertil Steril 2007
Effectiveness of EC and level
of postfertilization effects are
directly related.
If actual effectiveness turns out to be
more than 30-50% with 24 or more
hours of delay in administration, then
this strong evidence that EC also works
after fertilization.
Effectiveness of EC and level
of postfertilization effects are
directly related.
If EC works at all after 72 hours delay,
then it must be working by a
postfertilization mechanism.
What should patients be told
about Plan B?
Plan B: essential counseling points
 Same hormones present in some birth
control pills, in higher dose
 Used to prevent pregnancy after
intercourse
 More effective the sooner it’s taken
 Probably not effective after 72 hours
 Effectiveness- probably no more than 72%
 Much less than any other method
 Taking both pills at once is as effective as
taking them 12 hours apart
Plan B: essential counseling points
 Typical side effects
 Nausea and vomiting (23%)
 Abdominal pain (18%)

 Headache (17%)

 Fatigue (17%)

 Delayed or altered menses (26%)

Plan B: essential counseling points
 May operate after fertilization (unknown
proportion of cycles)
 =postfertilization effect
 The more effective it is, the more likely it is
operating after fertilization.
When is conception/pregnancy?
 “the beginning of pregnancy, usually taken to
be the instant that the spermatozoon enters an
ovum and forms viable zygote.”
-Mosby’s Medical Dictionary, 2002
 “...implantation of the blastocyst in the
endometrium”
-Stedman’s Medical Dictionary, 2000
Conception and onset of pregnancy
 Defined differently by different medical
authorities.
 Those who have a particular viewpoint cite one
set of authorities and ignore the other set.
 The more relevant issue is what do
patients understand.
 National polls: about 50% of women believe
that “life” begins at conception/fertilization.
Informed consent
 Requires that terms be used that clearly
communicate to patients’ understandings,
beliefs, and values.
 Insufficient, and potentially misleading to
use the word “pregnancy” as beginning at
implantation and assume that a patient
shares this definition.
Current marketing of Plan B
 Package insert
 “Plan B works like a birth control pill to prevent
pregnancy mainly by stopping the release of an egg
from the ovary. It is possible that Plan B may also work
by preventing fertilization of an egg (the uniting of sperm
with the egg) or by preventing attachment (implantation)
to the uterus (womb), which usually occurs beginning 7
days after release of an egg from the ovary. Plan B will
not do anything to a fertilized egg already attached to
the uterus.”
FDA approval process for OTC
status of Plan B
Abbreviated time line for Plan B
 July 1999: Plan B approved as
prescription
 Citizen’s petitions for OTC status, state
efforts for pharmacist dispensing
 April 2003: Company applies for OTC
status
 December 2003: FDA Advisory Committee
meeting
FDA hearing
 Advisory committee for reproductive health
drugs: 11 members
 Advisory committee for OTC drugs: 13
members
 Special consultants: 4 persons
 Mix of science, theater, and politics
 End of day: vote
FDA Advisory committees vote
 Final vote for approval for OTC status
 23 yes
 4 no
 Stanford: Overestimated effectiveness information
and inadequate information for informed consent for
postfertilization effects (at time of review)
 Hager: Insufficient information re OTC safety for
adolescents
 Crockett: Should remain prescription for physician
counseling for contraception
 Cantilena (Chair): Label comprehension studies
inadequate
Abbreviated time line for Plan B
 May 2004: Against internal advice of staff,
the FDA director of CDER denies OTC
status, citing (only) concerns about safety
of use in adolescents.
 Investigations begin of decision being
made for political reasons
 July 2004: Company applies for OTC
status for women age 16 and older.
Abbreviated time line for Plan B
 July 2005: Senators Patty Murray and Hilary
Clinton allow the nomination of Lester Crawford
as FDA Commission to proceed with promise
from HHS Secretary Mike Leavitt that Plan B
decision will be made by September 1.
 August 2005: Susan Wood, Director of FDA
Office of Women’s Health, resigns.
 September 2005: Lester Crawford resigns.
Abbreviated time line for Plan B
 Fall 2005: Andrew von Eschenbach nominated
for FDA Commissioner; nomination placed on
hold by Senators Patty Murray and Hilary Clinton
until FDA acts on Plan B OTC application.
 August 24, 2006: An FDA memo from acting
FDA Commissioner Dr. von Eschenbach
approves the application of Plan B for OTC
status for women age 18 and over- the day
before Senate confirmation hearings.
Conditions for marketing Plan B
 Only sold in facilities that can sell prescription
drugs
 Sold from behind the counter
 OTC upon ID proof of 18 and over
 Company will
 Engage in educational campaigns for health
professionals and public
 Do annual survey of health professionals
 Use existing data sources to monitor pregnancy rates,
abortion rates, STI rates
 Monitor point of purchase with anonymous shoppers
My summary
 The approval process was amazingly political.
 The drug meets criteria for OTC safety.
 Effectiveness is substantially overestimated on
product literature and advertising.
 Company advertising is misleading.
 What will be the effects of having Plan B more
widely available?
What are the social effects of EC?
Putative effects of EC
 Advocates claim great social benefits
 Prevention of thousands of unplanned
pregnancies and related costs
 Based on number of doses sold, and average
number estimated pregnancies that may have
occurred if not used
 Underlying assumption: no other change
in sexual and contraceptive behavior
 Is there any evidence for these claims?
Committee on Adolescence, Pediatrics 2005
Does EC reduce unplanned
pregnancy or abortions?
 RCT China, 2000 women
 Women using condoms, intervention
group given EC (mifepristone)
 Pregnancy rates (1 year)
 EC group 4.6%
 Control group 3.9%

 Women in EC group more likely to use EC

Hu et al, Contraception 2005

Does EC reduce unplanned
pregnancy or abortions?
 Community intervention in Lothian,
Scotland (estimated n=85,000)
 Provided 5 free courses of EC
 Estimated17,800 took this offer
 45% used EC at least once

 Abortion rates did not change in relation to

neighboring areas of Scotland

Glasier et al, Contraception 2004

Does EC reduce unplanned
pregnancy or abortions?
 RCT n=2117 women in California
 Ages 15-24
 Usual care (clinic access)
 8.7% pregnancy rate
 Pharmacy access
 7.1% pregnancy rate
 Advanced provision
 8.0% pregnancy rate
Raine et al, JAMA 2005
Does EC reduce unplanned
pregnancy or abortions?
 RCT n=111 women
 Ages 14-20
 Usual care
 18% pregnancy rate (6 months)
 Advanced provision of Plan B
 7% pregnancy rate (6 months)
 Not statistically significant

Belzer et al, J Adolesc Health 2003

Does EC reduce unplanned
pregnancy or abortions?
 RCT n=111 women
 Ages 14-20
 Usual care
 45% “unprotected sex” (12 months)
 Advanced provision of Plan B
 69% “unprotected sex” (12 months)
 Statistically significant

Belzer et al, J Ped Adolesc Gyn 2005

Does EC reduce unplanned
pregnancy or abortions?
 UK
 Abortion rates 11 per 1000 women in 1984
 EC made OTC in 2001

 Hundreds of thousands of doses sold

 Estimated should prevent about 1/3 of abortions

 40 million pounds spent to educate teens

 Abortion rates 17.8 per 1000 women in 2004

 Similar statistics from Sweden

Glasier, British Med J; 16 Sep 2006
Qualitative studies of EC use
 Pharmacists and patients
 UK

 New York City

 Generally like the idea of EC, but
 Concerns about decreased use of
“regular” contraception
 Concerns about increased risk taking

Bissell et al, Soc Sci Med 2003;

Karasz et al Ann Fam Med 2004
Qualitative studies of EC use
 “Perhaps we should pay attention to
these concerns of physicians,
pharmacists, and users with further
qualitative and quantitative research
on the long-term outcomes of EC
provision, rather than simply
dismissing all such concerns as
irrational moral qualms…”
Stanford, letter. Ann Fam Med 2004
Social effects of EC use
 “If you are looking for an intervention that
will reduce abortion rates, emergency
contraception may not be the solution, and
perhaps you should concentrate most on
encouraging people to use contraception
before or during sex, not after it.”

Glasier, British Med J; 16 Sep 2006