Article Type: Review Article

Accepted Article
Current controversies with oral emergency contraception: a review

Running title: Current controversies with oral emergency contraception

Cameron ST 1, Li HWR 2,4, Gemzell-Danielsson K 3,4

1. Chalmers Sexual and Reproductive Health Centre, Edinburgh, United Kingdom

2. Department of Obstetrics and Gynaecology, University of Hong Kong, Queen Mary
Hospital, Hong Kong
3. Department of Women's and Children's Health, Division of Obstetrics and Gynaecology,
Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
4. Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The
University of Hong Kong – Shenzhen Hospital, Shenzhen, P.R. China

Correspondence to:
Dr. Sharon T. Cameron
Chalmers Sexual and Reproductive Health Centre, 2A Chalmers Street, Edinburgh EH3 9ES,
United Kingdom
Telephone: +44 131 536 1070
Fax: 00 44 131 536 1609
Email: sharon.cameron@ed.ac.uk

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/1471-0528.14773
This article is protected by copyright. All rights reserved.
 Abstract
Emergency contraception (EC) is a method to be used in the case of unprotected sexual
Accepted Article
intercourse, failure of a regular contraceptive method, or after rape to try to prevent an
unintended pregnancy. Oral EC remains surrounded by controversy, much due to myths and
misconceptions amongst the public, policy makers and healthcare providers. This has
resulted in restrictions on its availability in many parts of the world and restrictions on
women’s access to it. The aim of this article is to provide an evidence-based view on some
of these common controversial issues surrounding oral EC in clinical practice.

Keywords: emergency contraception, ulipristal acetate, levonorgestrel, postcoital

contraceptive agents

Tweetable abstract: Controversy about emergency contraception restricts access for

women.

Introduction
Emergency contraception (EC) can be provided as either an oral hormonal method or the
copper intrauterine contraceptive device (Cu-IUD). The Cu-IUD is the most effective EC with
failure rates of less than 0.1% (1,2). In contrast to oral methods, the Cu-IUD has both pre
and post fertilisation effects (3) can be used over a wider time period than oral EC and can
be retained for highly effective ongoing contraception (Table1). However, the Cu- IUD may
not be the preferred or suitable method for all users and is also more provider-dependent.
Hence oral EC remains the more commonly used approach.

The first oral EC introduced in the 1960’s consisting of high oral doses of estrogens was
phased out due to a high incidence of estrogen-related side effects. In 1974, a combination
of ethinylestradiol (100 μg) and dl-norgestrel (1 mg) administered within 72 hours of
unprotected sexual intercourse (UPSI) with a repeat dose 12 hours after was introduced (2).
This ‘Yuzpe’ regimen was gradually replaced by levonorgestrel (LNG) in the 1990s, as fewer
side effects and higher clinical efficacy with LNG were demonstrated (4). A single dose of
LNG (1.5 mg) administered within 72 hours of UPSI is the recommended regimen for LNG-EC

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 (5). Although licensed for use within 72 hours, there is evidence that efficacy may be
maintained up to 96 hours post UPSI (6).
Accepted Article
In recent years, a single 30 mg oral dose of ulipristal acetate (UPA), a progesterone receptor
modulator (PRM), has been introduced as EC. The UPA-EC regimen is slightly more effective
than LNG as shown by a meta-analysis (n=3242) of two randomised controlled comparative
trials (7,8). The efficacy of UPA-EC is maintained up to 120 hours after UPSI (8,9), which is
the recommended time limit in the product license.

Mifepristone is another PRM which was first studied as EC in 1992 (10,11) at a dose of 600
mg taken within 72 hours of UPSI. Subsequently, equivalent effectiveness as EC was
confirmed with lower doses at 10-50 mg (12). According to the latest Cochrane review,
mifepristone at mid-dose (25-50 mg) ranks top among the oral EC methods in terms of
efficacy (1). However, mifepristone preparations at EC dose are available only in a few
countries (13).

Mechanisms of action of EC
What are the mechanisms of action of EC?
All oral methods of EC are capable of delaying ovulation. As sperm survive in the female
reproductive tract for up to five days, oral EC can prevent pregnancy if it can delay ovulation
long enough for sperm to have lost their fertilising capacity or are no longer viable (5).

The Yuzpe regimen is thought to act by inhibiting or delaying ovulation (14,15). Other post-
ovulatory mechanisms of action have been proposed based on epidemiological modelling
(16,17), but such evidence was only circumstantial. Some minor morphological or molecular
changes in the endometrium following administration of Yuzpe have been reported in some
studies (18,19,20) but not others (15), and the actual clinical significance of these alterations
is uncertain. The high dose of progestogen in Yuzpe may also thicken the cervical mucus
and impair sperm penetration, but this is probably not relevant in the context of EC which is
used some time after the UPSI (21). There are no reported data on the direct effect of the
Yuzpe regimen on sperm or fallopian tube function.

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 LNG-EC acts by blocking the LH surge and hence inhibiting follicular growth or delaying
rupture. However, it is not effective if administered after the onset of the LH surge
Accepted Article
(22,23,24). In-vitro studies showed that LNG at concentrations relevant for EC had no
significant effect on sperm function nor fertilisation (25,26,27), nor on endometrial
receptivity and embryo attachment (28, 29). Although one in vitro study showed that it
might inhibit muscular contractility of the fallopian tube (30), other data suggested that LNG
inhibited ciliary beat frequency and muscular contractility only at supra-pharmacological
concentrations (31). Overall, LNG probably has minimal post-ovulatory actions, if any, and
this may explain the observation that LNG is only effective for EC if administered pre-
ovulatory but not post-ovulatory (31,32).

Mifepristone at a dose of ≥10 mg delays follicular development and ovulation, although

ovulation usually takes place eventually (33,34). A small pilot study showed that even when
mifepristone at a dose of 200 mg was administered after the onset of the LH surge,
ovulation was not consistently blocked (35). In vitro studies suggested that mifepristone at
the EC dose may inhibit endometrial receptivity (28,29) and muscular contractility of the
fallopian tube (28), but not sperm function or fertilisation (26, 28,29,36).

UPA exerts its EC action by blocking or delaying ovulation, and such an effect of UPA
remains evident even when administered after the onset of the LH surge but before the
peak (37). Follicular rupture can be delayed by at least five days after intake of UPA in 100%
of cases when given before the onset of LH surge and in 79% after the onset but before the
LH peak (38). This means that UPA has a wider window of action than LNG and remains
effective in the immediate pre-ovulatory phase when the risk of conception is greatest,
hence explaining its higher efficacy compared to LNG in clinical trials (8). Postovulatory
administration of UPA at the EC dose may induce some immunohistochemical and
molecular changes in the endometrium (39), but other in vitro studies have shown that UPA
at concentrations relevant for EC do not interfere with embryo attachment to the
endometrium (40,41). UPA at pharmacological concentrations can suppress ciliary beating
and muscular contractility in fallopian tube (43), as well as modulate sperm function by
inhibiting sperm hyperactivation, progesterone-induced acrosome reaction and calcium
influx (26). However, the clinical relevance of these in vitro findings remains uncertain.

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 Sperm may only take minutes to reach the fallopian tube after UPSI (23), and this window is
too short for the sperm-targeted action in the EC context. Furthermore, a recent clinical
Accepted Article
study (n=693) indicated that UPA had significantly higher efficacy as EC when administered
before than after ovulation (42), which implied that post-ovulatory mechanisms may not
contribute much, if at all, to the action of UPA-EC.

Does EC induce a miscarriage or an ectopic pregnancy?

In theory any post-fertilisation mechanisms of action of oral EC, if they exist, would act
before establishment of pregnancy, i.e. before embryo implantation. Hence, EC is not an
abortifacient. The rate of miscarriage in clinical trials of EC is no higher than what one might
expect to observe in the general population (8, 43). Although in vitro studies might suggest
some action of EC on tubal function, a systematic review showed no higher incidence of
ectopic pregnancy after oral EC than in the general population (44).

Are mechanisms of action important to users?

Survey data from Europe and the US show that up to 40% of women report not knowing
how oral EC works [45,46]. There is little data on whether EC users are concerned how EC
works. A survey of 500 women in the UK showed that most were hypothetically prepared to
use an EC pill that might prevent or even disrupt implantation (47). Clearly a method that
worked by disrupting implantation may raise legal issues in many settings, but would be
permissible in countries where ‘menstrual induction’ (i.e. evacuation of the uterus in
women with delayed menses without laboratory confirmation of pregnancy) is permitted,
such as China (48).

Effectiveness of EC
How effective is EC?
There has never been a placebo-controlled trial of oral EC because of ethical concerns over
those assigned to the placebo group, since EC is widely recognised to reduce unintended
pregnancies. This is inferred in most comparative clinical trials where the pregnancy rates
observed after EC use are lower than that might have occurred in the absence of EC (based
upon data for the risk of conception on the respective cycle days). However, calculations of
expected pregnancy rates falsely assume that we can accurately determine the phase in the

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 menstrual cycle when intercourse took place, that women have had just one episode of
UPSI and that sperm have entered the reproductive tract. In reality, this may not be the case
Accepted Article
(5,16,17). In a randomised trial (n=1899), UPA was estimated to have prevented 67% of
expected pregnancies while LNG was estimated to have prevented 52% (8). The reported
pregnancy rates in the comparative clinical trials of UPA and LNG EC were around 1 and 3%
respectively compared to the expected rate of 4 % (in the absence of EC) (5,8). Studies have
also demonstrated lower pregnancy rates with earlier administration of EC after UPSI, which
may be because the woman is less likely to have already ovulated (5).

Does obesity impact on effectiveness of EC?

A secondary analysis of two RCTs comparing LNG and UPA-EC demonstrated that obesity i.e.
body mass index (BMI) ≥30kg/m2 increased the risk for pregnancy after EC, and the risk was
more pronounced with LNG than UPA (4-fold versus 2-fold)(49). The same trend was
concluded in a pooled analysis of a phase III study of UPA (50). However, the trials were not
designed to address the issue of BMI on efficacy of EC. In addition, the numbers of women
with obesity were low, as were the number of pregnancies in this group. Also, in many cases
height and weight had been self-reported. Furthermore, previous studies of LNG-EC had
failed to show an impact of BMI upon pregnancy rate (51, 52). In 2014, the EMA reviewed
the available data and concluded that the data were not sufficiently robust to discourage
women with obesity from using either UPA or LNG-EC (53). More recently, a pooled analysis
of RCTs of LNG conducted by WHO (n=6873) reported higher pregnancy rates among
women with obesity compared to women of normal weight (although this was only
statistically significant with regression analysis and adjustment for several factors) (54).
There is also pharmacokinetic data indicating that LNG takes a longer time to achieve steady
state levels in women with obesity compared to those of normal BMI, which can be
overcome by doubling the dose of LNG (55). Conversely, the pharmacokinetics of UPA are
not affected by obesity (56). It is very unlikely that there will be a definitive RCT comparing
the efficacy of EC in women with obesity versus those with normal weight, so for now the
uncertainty regarding impact of BMI on efficacy of EC remains. Nonetheless, the current UK
guideline recommends that women weighing >70 kg or with BMI >26 kg/m2 should be
offered UPA-EC or consider a double dose (3mg) of LNG-EC, although it is not known which
of these two options is more effective (5).

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 How good is advance provision of EC at preventing unintended pregnancy at population
level?
Accepted Article
Population studies and clinical trials of advance provision of EC (supply to keep at home in
case of need) indicate that use of EC does not reduce rates of unintended pregnancy or
abortion at population level. A Cochrane review of six RCTs of over 6300 women with
advance supplies of EC compared to standard access failed to demonstrate any reduction in
pregnancy rates at 3, 6 or 12 months (57). This is probably because many women under-
estimate their risk of pregnancy and do not take EC after UPSI even if an advanced supply is
provided (58).

Safety of EC
Is EC generally safe to use?
In contrast to the Yuzpe regimen, side effects associated with use of LNG-EC or UPA-EC are
infrequent, minor and generally well-tolerated. Serious adverse effects are very rare (5,8).
The pattern of side effects (nausea, headache, etc.) reported after UPA is similar to that
after LNG (8), and is similar for adults and adolescents (59). A review of the safety of UPA-EC
by the European Medicines Agency (EMA) (53) concluded that UPA was so safe that a
change in classification status from prescription to non-prescription was recommended and
this has been widely adopted in most European countries (13).

Does EC exposure have a harmful effect on a pregnancy?

A prospective cohort study showed no association between the use of LNG-EC and the risk
of major congenital malformation, pregnancy complications or any other adverse pregnancy
outcomes (60,61). Data regarding the effects of UPA on pregnancy outcome are inevitably
limited due to few pregnancies reported after UPA-EC so far, and that many of these
unintended pregnancies were voluntarily terminated. However, the available data from
over one million women who used UPA in the clinical trials and during post-marketing
surveillance have been consistent with no increased risk of miscarriage, ectopic pregnancy
or congenital abnormality in babies after UPA exposure [43].
Regarding the Yuzpe regimen, there is some reassurance extrapolating from a meta-
analysis of 12 available prospective studies on around 6000 exposed women, that did not
find any statistically significant association between oral contraceptive use in early

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 pregnancy and fetal malformation (62).
Indirect evidence from in vitro studies also showed that LNG or UPA at EC doses had no
Accepted Article
effect on human blastocyst viability (28,29,41) in spite of sufficient time being allowed for
the embryo to undergo any degenerative changes that LNG or UPA could possibly cause
within the culture system.

Does EC have an adverse effect on breastfeeding?

EC is not required before 21 days postpartum (63). Women who take LNG whilst
breastfeeding can be advised that they can continue to breastfeed (63,64). A recent
systematic review suggested no adverse effect on breastfeeding performance or infant
outcomes with the use of progestogen-only contraception (65). Guidelines therefore advise
that women can continue to breastfeed after LNG for EC (66,67,68).

There are no data on effects of UPA on breastfeeding nor on infant outcomes. Since UPA is
lipophilic, secretion to breast milk could be expected. However, levels are likely to be
extremely low and adverse effects are unlikely. The manufacturer advises women to discard
breast milk for seven days after UPA which has been endorsed by UK and WHO guidelines
(5,66,67). In contrast, US guidelines advise discarding milk for 24 hours only (68). Even this
advice may be overly cautious since studies of another PRM (mifepristone) have shown that
following 200mg of mifepristone (which is four times the EC dose), the peak mifepristone
levels in breast milk are extremely low (less than 1.5% of maternal levels) (69).

Does use of EC increase risky sexual behavior?

There were reservations among users and healthcare providers against making oral EC
available without prescription mainly because of the myths that easier access to EC might
compromise the use of regular contraception or promote risky and irresponsible sexual
behaviours (57). However, numerous studies showed no evidence that availability of EC
resulted in women abandoning regular contraception in favour of EC (57). In addition,
advance provision of EC does not appear to increase the frequency of UPSI or sexually
transmitted infections (57).

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 Is it safe to use oral EC more than once in the same cycle?
Since follicular development and ovulation are only postponed after intake of EC, women
Accepted Article
are at risk of becoming pregnant if further acts of UPSI take place in the same cycle (5); such
risk has been reported as three- to four-fold compared to no further UPSI (1,49). Based on
the half-life of LNG and UPA, repeat use of EC is recommended in the case of further UPSI
beyond 24 hours from the last EC use (66).
A study of women taking peri-coital LNG-EC repeatedly i.e. as required either before or
within 24 hours of UPSI as their main method of contraception, reported a pregnancy rate
of 11 per 100 women-years. It was well tolerated with a low incidence of side effects, and
with an efficacy that is better than no method (70). Nevertheless, women should be
informed that repeated EC use is less effective than a regular method of contraception and
may result in irregular bleeding (67).

In a biomedical study where UPA at EC dose was administered every five or seven days over
a period of eight weeks, ovulation was delayed but eventually happened in most women
(71). This was associated with irregular bleeding. Assessments of endometrium showed
morphological changes associated with PRM exposure. Tests of liver function, haematinics
and thrombotic markers were also normal. The EMA reviewed the data and concluded that
repeat administration of UPA in the same cycle was safe (53).

Contraception after EC
Do women want to start effective contraception after EC?
It is important that EC users who will remain sexually active start an effective method of
contraception as soon as possible. If women attend a family planning service or a general
practitioner for EC, then they can be provided with ongoing contraception at this same visit.
Studies from the UK suggest that up to 50% of women accessing EC from a family planning
service are provided with a contraceptive method at this time (72, 73), and a study from
Sweden showed that over half of women receiving UPA were using effective contraception
six months later (74). Of course, women are increasingly choosing to access EC from the
pharmacy (in countries where this is available without prescription) (13, 75), but most
pharmacists cannot provide ongoing hormonal contraception without a prescription. In a

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 survey of women attending UK pharmacies for EC, 64% indicated that they would value the
opportunity to receive a supply of contraception from the pharmacy (76). A pilot study
Accepted Article
showed that women provided with a one-month supply of a progestogen-only pill along
with EC from a pharmacy were more likely to be using effective contraception two months
later than women attending pharmacies where they only received advice on where to
obtain supplies of contraception (56% vs 16%). Larger robust studies are needed to
determine if this strategy can increase the uptake of effective contraception after EC from
the pharmacy (77).

Is it safe to ‘quick start’ hormonal contraception immediately after EC?

Guidelines advise that after LNG-EC women can start hormonal contraception immediately,
based on the assumption that LNG will not interact with hormonal contraception (5).
However, UPA is a PRM and so there is a theoretical concern about interaction with
progestogen-containing hormonal contraception by competition at the progesterone
receptor, as has been shown for other PRMs (78). Two biomedical studies have addressed
the impact of UPA on hormonal contraception in the presence of a dominant follicle. One
showed no adverse impact of UPA on the ability of combined oral contraception initiated
one day later to induce ovarian quiescence, but this study was not designed to examine any
impact of combined oral contraception on the ability of UPA to delay ovulation (79). The
other (80) reported that UPA did not affect the contraceptive action of a desogestrel-only
pill on cervical mucus or ovarian quiescence. However, an ovulation rate of 45% within 5
days was reported among women quick-started on the desogestrel-only pill after UPA,
compared to 3% among women taking placebo pills. Hence, immediate start of a
desogestrel-only pill appears to counteract the contraceptive effect of UPA and expose the
individual to the same risk of pregnancy faced without use of EC. This was a small study of
one type of hormonal contraception, but it is biologically plausible that this effect may apply
more broadly. Thus, it is advisable to delay initiation of hormonal contraception for at least
five days after UPA (5), although some suggest that it may be more biologically correct to
count the five days from the episode of UPSI (life span of sperm) rather than from intake of
UPA (81). Although UK guidelines advise that the levonorgestrel releasing intrauterine
system should not be inserted until pregnancy has been excluded, there are some data to

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 suggest that starting this method with LNG-EC may be a reasonable option for some women
(82). More research however is required.
Accepted Article
The future: can we develop a more effective EC?
Prostaglandins play a critical role in follicle rupture. Preliminary data suggested that addition
of meloxicam (a cyclo-oxygenase inhibitor) to LNG may potentiate its effect in suppressing
ovulation (83), but whether the same applies to UPA is uncertain, and needs to be explored
in large robust trials.

‘Contragestion’ was the term used by contraceptive researchers in the 1980’s to describe a
potential method that could remain effective after ovulation to prevent or disrupt the
establishment of a very early pregnancy at the end of the luteal phase (84,85). This conveys
the concept of an ‘emergency’ method that works throughout the cycle in order to prevent
pregnancy. Mifepristone combined with misoprostol may potentially be developed for this
purpose in countries where this is allowed (86).

CONCLUSIONS
This article provides an evidence-based view on the current oral EC methods (summarised in
Table 1). Myths and misconceptions surrounding oral EC have hampered availability, access
to, and use of EC by women. The best evidence shows that oral EC works by delaying
ovulation (if that has not already taken place), is not as effective as many might believe, is
extremely safe and does not lead to women abandoning regular contraception or increased
prevalence of sexually transmitted infections. So what has all the controversy been about?
All women deserve a second chance to prevent an unintended pregnancy and we need to
develop strategies to maximise the effectiveness of EC. Firstly, use of the Cu-IUD as the
most effective EC should be considered. Furthermore, women should be advised to avoid
further UPSI in the same cycle after oral EC, and should acquire an effective method of
contraception as soon as possible.
More research is required to explore provision of ongoing contraception with oral EC from
the pharmacy, and also of the possible impact of obesity on oral EC. Finally, women deserve
a more effective oral EC, which can prevent pregnancy even after ovulation has occurred
and which could potentially also be used “on demand”. This could be an EC that prevents

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 implantation, but could also be a contragestive pill that women could take as and when
required and that works throughout the cycle, although this remains controversial.
Accepted Article
Contributions to authorship
The authors jointly conceived the idea for the article, contributed to the article and revised
and approved the final draft.

Funding
None

Disclosure of interests
All authors have previously received research funding or supplies of UPA from HRA Pharma
for studies alluded to in this paper. The ICMJE disclosure forms are available as online
supporting information.

Ethics
Not applicable

Acknowledgements
We would like to acknowledge the Sanming Project of Medicine in Shenzhen for supporting
research at the Reproductive Medicine Center, The University of Hong Kong – Shenzhen
Hospital, under guidance by Professor Kristina Gemzell-Danielsson.

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 Table 1. Current methods of emergency contraception (in order of increasing effectiveness).
Accepted Article
Method and regimen Class of drug Recommended Mechanism(s) of Specific notes on use
time limit after action
unprotected
intercourse

Yuzpe method (Two Combined Up to 72 hours • Inhibiting or • Can be made up by

doses of ethinyl- estrogen and delaying ovulation multiple tablets of
estradiol 100 μg + dl- progestogen combined oral
norgestrel 1 mg contraceptive pills
administered 12 hours • Nausea and vomiting is
apart) a common side effect
• Needs to be
administered in two split
doses

Levonorgestrel 1.5 mg Progestogen Up to 72 hours • Inhibiting or • Fewer side effects than

single dose (license limit) delaying ovulation Yuzpe method
Up to 96 hours • Administered as a single
(unlicensed) dose
• More effective than
Yuzpe
Ulipristal acetate 30 Progesterone Up to 120 • Inhibiting or • Fewer side effects than
mg single dose receptor hours delaying ovulation Yuzpe method
modulator • Possibly disturbs • Administered as a single
sperm function dose
• Possibly disturbs • More effective than
tubal function levonorgestrel
Mifepristone Progesterone Up to 120 • Inhibiting or • More effective than
25-50 mg single dose receptor hours delaying ovulation levonorgestrel
modulator • Possibly disturbs • Available at EC dose in
tubal function few countries only
• Possibly disturbs
endometrial
receptivity
Intrauterine Up to 120 • Copper ions toxic • Can be retained until
Copper intrauterine contraceptive hours to sperm and pregnancy excluded or
device method Or up to 120 oocytes so can be kept for ongoing
hours after the prevents effective contraception
earliest fertilisation
estimated date • Endometrial
of ovulation changes may
prevent
implantation

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