Experience with oral emergency contraception since the OTC switch in Germany

The available data on the mechanism of action of the two active ingredients are extensive. For the search term “emergency contraception” alone, there are 3318 publications in PUBMED (1947–24.06.2016) and 1354 of which are on the topic of mechanism of action of emergency contraceptives (1953–24.06.2016). From 2002 onwards, there is a sharp increase in publications on the subject mechanism of action. According to the most recent studies, the mechanism of action of oral emergency contraceptives is as follows: if taken early enough, UPA (ellaOne^®) and LNG (e.g., PiDaNa^®) delay ovulation [1]. Through agonistic effects on the progesterone receptors of the hypothalamus–pituitary–gonadal axis, UPA and LNG exercise negative feedback and thus suppress the release of FSH and particularly LH by the pituitary [2, 3]. Through the suppression and delay of the LH peak, an important trigger of ovulation is missing, thus resulting in inhibition of ovulation.

UPA, as selective progesterone receptor modulator (SPRM), also has additional effects. Pharmacodynamic studies were able to show that UPA also has ovulation-inhibiting action during the LH increase [4]. When the LH increase occurs in the progesterone receptor, agonist LNG loses its effect. The LH increase (approximately 2 days before ovulation) marks the beginning of the most fertile phase of the cycle. The likelihood of conception on these 2 days is about 30% [5]; however, on account of the variability of ovulation, the time of this phase cannot be predicted [6].

A further additional effect of the SPRM UPA is on the pre-ovulatory progesterone surge. An increased concentration of follicular progesterone together with increased oestrogen and LH levels is a further essential trigger of ovulation [7, 8]. According to pharmacodynamic studies, UPA has an inhibitory effect on the pre-ovulatory progesterone surge [4].

On the follicular level, selectively antagonistic effects of the SPRM UPA are also relevant. Studies in animals showed evidence of the direct antagonistic effects on the follicular level [9]. It was shown on receptor level that activation of the follicular progesterone receptors is necessary for activation of the signal cascade which ultimately leads to ovulation. UPA blocks this signal cascade and can have an additional ovulation-inhibiting action via this direct follicular effect. On the other hand, LNG, as pure progesterone receptor agonist, does not block the follicular, progesterone receptor-mediated signal cascades which lead to triggering of ovulation.

On account of these three additional effects, the SPRM UPA is superior to the progesterone receptor agonist LNG with regard to inhibition of ovulation [4]. UPA is also effective in the most fertile phase of the cycle, during the LH increase, up to shortly before ovulation. The effective window of LNG on the other hand ends 2–3 days before ovulation with the start of the LH increase. The development of UPA as emergency contraceptive thus represents a considerable advance in contraception, particularly on account of its diverse mechanisms of action and low side-effect rate [10].

The analysis of the sale figures for oral emergency contraceptives shows, since the switch to OTC status approximately 60,000 packs of hormonal emergency contraceptives per month is dispensed by pharmacies. In comparison with the era of prescription-only status, the market has increased by almost 50% [11]. A look at the development of the market of oral emergency contraceptives from 2014 to 2015 by active ingredient shows a growth in the market from March 2015 onwards [11]. With the removal of the prescription-only requirement in March 2015, there was a sharp increase in the number of morning-after pills sold from about 40,000 per month to approximately 52,000.

Looking at the market growth by active ingredient, we see that the trend set in motion by the gynaecological experts has continued: since 2013 UPA has been the standard for emergency contraception for German gynaecologists [12]. After the switch to OTC status, the superior efficacy of UPA over LNG is still utilised. About two-thirds of the morning-after pills sold and contain the SPRM UPA [11].

Looking at the user rate, we see that in 2015, 3.9% of the women between 15 and 49 years of age in Germany used the morning-after pill [13].

The European comparison (Fig. 1) shows that in spite of the market growth, oral emergency contraceptives are still used relatively seldom in Germany. The top users in Europe are Sweden, Norway, and France with more than 11% of all 15–49-year-old women. The rate of 3.9% in Germany is well below the EU average of 6.7%.

Estimates show that only 30% of women in Germany use emergency contraceptives after unprotected intercourse to prevent an unintended pregnancy [11, 14, 15, 22] and they usually only use emergency contraceptives once in a lifetime. In a representative survey by the German Federal Centre for Health Education, only 2% of all users reported that they had taken the morning-after pill more than once [16].

According to a recent survey, men and women report that 86% of sexual encounters take place at weekends [17]. The likelihood of contraceptive failures at weekends is correspondingly great. Through the OTC status, women do in fact make use of the rapid access to oral emergency contraception [18, 19]. Thus, the percentage of oral emergency contraceptives sold at the weekend has increased from 7% when the prescription-only requirement was in place to currently 28% (Fig. 2). This means that after unprotected intercourse, more women now make use of the easier access to emergency contraception at weekends.

A feared fall in the age of emergency contraceptive users has not occurred: the age of the users of oral emergency contraceptives has not changed as a result of the switch to OTC status [20, 21]. More than two-thirds of users are still over 20 years of age (Fig. 3).

In more than half of the cases, the reasons for taking hormonal emergency contraceptives are failure or forgetting of contraceptive precautions. In a European-wide survey by BVA Healthcare, 39% of the German women interviewed reported condom failure, 34% missed pills, 21% no contraception, 9% a contraceptive pause, and 9% other reasons [22]. Thus, the most common reason for using oral emergency contraceptives is not “no contraception” but failure or forgetting of contraceptives.

Hence, unprotected intercourse occurs mainly as a result of contraceptive failure. This also confirms a survey by the German Federal Centre for Health Education on unintended pregnancies. In this survey, 35.8% of the women who had become pregnant unintentionally stated that they had in fact regularly used contraceptives [23] with 52% using oral contraceptives and 31% using condoms.

Doctors—particularly gynaecologists—continue to play an important role for users of oral emergency contraceptives in spite of the fact that the prescription requirement has been lifted. Pharmacies have the option of referring a customer to a doctor at any time, particularly if unclear issues arise during their counselling, e.g., in the case of medical conditions, such as an increased risk of thromboembolic events, severe liver impairment, or epilepsy.

In 2015, 17% of oral emergency contraceptives were dispensed on prescription [24]. Thus, even after the switch to OTC status, some women and girls go directly to a gynaecologist. This is partly because of ignorance about the OTC status of the morning-after pill but also to obtain a prescription for the purpose of reimbursement. In the process of the switch to OTC status for oral emergency contraceptives, the “Fourteenth Ordinance on Amendment of Prescribing of Medicinal Products” [Vierzehnte Verordnung zur Änderung der Arzneimittelverschreibungsverordnung] initiated a corresponding amendment of Article 24a of Book Five of the German Social Security Code (SGB V). This means that doctors can also prescribe non-prescription emergency contraceptives on a statutory health insurance prescription. For women under the age of 20, emergency contraceptives are reimbursable. For women aged 18–20, there is a prescription fee of €5. In spite of regulation of the reimbursability, 17% of oral emergency contraceptives prescribed 12% were prescribed on a private prescription [24].

Further reasons why some women go directly to a gynaecologist after unprotected intercourse may be to have an unplanned pregnancy ruled out with certainty or to use a contraceptive method regularly in the future [25].

The main source of information about the morning-after pill is still the doctor even after the switch to OTC status. This is the result of a recent survey [26]. Almost every second, woman in Germany (44%) who sought information about the morning-after pill consulted a doctor for this purpose. Further popular sources of information are search engines (22%), online health websites (18%), and pharmacy staff (16%).

According to the currently available data, the mechanism of action of oral emergency contraceptives is inhibition of ovulation with delay of ovulation [4]. On account of additional active ingredient properties (inter alia stabilisation of the follicle) of the SPRM UPA, the ovulation-inhibiting action of UPA is superior to that of LNG [4]. The high variability of ovulation must be taken into account [6].

Analysis of the two available comparative studies shows that the pregnancy rate on UPA is lower compared with the morning-after pill containing LNG [27]: 0.9% (UPA) vs 2.3% (LNG) when taken within 24 h after the unprotected intercourse, 1.4% (UPA) vs 2.2% (LNG) if taken within 72 h, and 1.3% (UPA) vs 2.2% (LNG) if taken within 120 h. For this reason, the morning-after pill containing UPA (ellaOne^®) has been the standard for German gynaecologists since 2013 [12].

Analyses (Lancet meta-analysis [27] and Cochrane Review [28]) of the only available two comparative studies [27, 29] show that UPA is superior to LNG.

The superior effectiveness is most marked when UPA is taken within 24 h after the unprotected intercourse (Fig. 4).

In its fact sheet, the WHO for the first time recognizes the superiority of UPA over LNG: the fact sheet states that if LNG is used within 72 h pregnancy can be prevented in 52–94% of the cases. Studies show that, if used within 72 h after unprotected intercourse, UPA can prevent unintended pregnancies in at least 98% of cases [30].

If LNG or UPA is not used soon enough before, ovulation pregnancy is possible in spite of emergency contraception. From the launching of 30 mg UPA for emergency contraception (ellaOne^®) in October 2009 to May 2015, 604 pregnancies were reported to the manufacturer [31]. The outcome of 207 (34.3%) of the reported pregnancies is not known. At the time of publication of the pregnancy data, 59 (14.9%) of the ellaOne^® pregnancies with known outcome were still ongoing and 60 (15.1%) pregnancies resulted in live births. These data show no indications of an increased risk of malformations or complications [31, 32]. Pregnancy in spite of oral emergency contraception is thus not an indication for termination.

According to the pharmacovigilance databases, 65% of pregnancies occurring after use of UPA were terminated [32].

Just under, 34% of all pregnancies in Germany are unplanned or unintended [23]. More than half of all unintended pregnancies are electively terminated [33]. In Germany, one in eight of all pregnancies is electively terminated [34, 35].

The absolute number of terminations of pregnancy in 2015 did not change significantly compared with 2014: in 2014, 99,715 terminations of pregnancy were performed and in 2015 99,237 [35]. However, when looking at the absolute figures on termination of pregnancy, changes in the population structure must also be taken into account. In 2015, many migrants entered Germany. Nothing can be said about the development of pregnancy terminations in relation to the population until the population figures for the year 2015 become available [36].

If we compare the figures for pregnancy terminations per 10,000 women in 2015 by federal state [35] with the rates of use of emergency contraceptive pills by 15–49-year-old women [11, 14], the following trend can be identified: in federal states with a low rate of use of emergency contraception, the pregnancy terminations per 10,000 women are higher. In Saxony-Anhalt, 86 of 10,000 women terminated a pregnancy in 2015. The percentage of 15–49-year-old women in Saxony-Anhalt who used the morning-after pill in 2015 was 1.95%. In Bavaria, on the other hand, the pregnancy termination rate is more than two times lower: in 2015, only 41 out of 10,000 women were electively terminated a pregnancy. Compared with Saxony-Anhalt, however, the rate of use of oral emergency contraceptives by 15–49-year-old women was 4.69% and thus more than twice as high (Fig. 5). These figures underline the importance of information and education about contraception and emergency contraception to avoid unintended pregnancies.

On the basis of the figures for 2015 on sale of emergency contraceptives [11], the failure rate [27], and terminations of pregnancy [35], it can be estimated that about 94% of the women who electively terminated a pregnancy had not taken any action to prevent a pregnancy after the unprotected intercourse. These figures show that more information and education on contraception and emergency contraception are needed. The lack of knowledge of the option emergency contraception in the population is confirmed by a recent survey of 1000 women and men aged between 16 and 39 [37]: only 53% mentioned the morning-after pill as a possible way of preventing an unintended pregnancy after unprotected intercourse. In the higher income brackets (monthly income €3000–3500), as many as 32% gave termination of pregnancy as an alternative.