Medicines For Women

8. Contraceptive Devices for Women: Implants, Intrauterine Devices and Other Products

Julie Craik  and Sam Rowlands2

(1)

Sandyford Sexual Health Service, NHS Greater Glasgow and Clyde, 2-6 Sandyford Place, Glasgow, G3 7NB, UK

(2)

School of Health and Social Care, Bournemouth University, R506 Royal London House, Christchurch Road, Bournemouth, BH1 3LT, UK

Julie Craik

Email: mail@fsrh.org

Introduction

The purpose of this chapter is to examine the health benefits, risks and side effects associated with contraceptive devices, specifically progestogen-only implants and intrauterine contraceptive methods. The combined transdermal patch, combined vaginal ring and progestogen-only ring will also be covered briefly. It is outside the scope of this chapter to cover other contraceptive methods such as contraceptive injectables, barrier methods and devices for the purposes of sterilisation. Additionally, new contraceptives are continually being developed (Bahamondes and Bahamondes 2014) but such methods will not be dealt with in this chapter.

The devices covered in this chapter are commonly referred to as long-acting reversible contraceptives (LARCs) as they are administered less frequently than once a month; the exception being the combined transdermal patch. Unlike short-acting methods, such as condoms and oral contraceptives, which are heavily dependent on user adherence for efficacy, once initiated, intrauterine methods and progestogen-only implants provide contraceptive cover for a number of years, without any particular action being required on the part of the user. Consequently their failure rates are very low.

Despite this, globally these methods are often under-utilised, with wide country variation (United Nations et al. 2013). For example a worldwide review of intrauterine contraception use showed that in Asia overall approximately 18 % of women aged 15–44 who are married or in a union used intrauterine devices (Buhling et al. 2014). The figures for North America and Oceania were 4.8 % and 1.1 % respectively (Buhling et al. 2014). Women’s choice of contraceptive will be driven by socioeconomic, environmental, cultural and individual factors; women’s knowledge of the method; ease of use; health professionals’ attitudes towards the method and concerns about safety and side effects (Belfield 2005).

In addressing the risks and benefits associated with these contraceptive devices, data are cited from different pharmacovigilance reporting systems. Conclusions about the safety of medicines cannot be made on the basis of these data and a listed reaction is not proof of causality. Case numbers from spontaneous reporting datasets cannot be used to estimate the prevalence of such events as such systems have no baseline data about the number of exposures. They have been included, in the same way as case reports, solely to illustrate that examples of such events exist.

It should be noted that not all the methods mentioned in this chapter are available in all countries. For example the transdermal patch is available in many European countries, the USA and Canada; it is not licensed for use in the New Zealand. Also, levonorgestrel implants are not licensed in the UK.

Progestogen-Only Implants

Norplant® was the first implant marketed for contraception. It comprised six small capsules, inserted into the arm in a fan formation, which released levonorgestrel. Norplant® was withdrawn from the UK and US markets in the 1990s in response to concerns about side effects and difficulties with removal: globally the product stopped being marketed in 2008 (Rowlands 2010a).

Subsequent devices were developed and the contraceptive implants available today consist of one or two flexible rods filled with etonogestrel (68 mg) or levonorgestrel (75 mg) (see Table 8.1).

Table 8.1

Summary of progestogen-only implants available

Name of implant

Progestogen

Number of rods

Length of rod (cm)

Dose per rod (mg)

Licensed duration of use (years)

Implanon®

Etonogestrel

1

4

68

3

Implanon NXT®/Nexplanon®a

Etonogestrel

1

4

68

3

Jadelle®

Levonorgestrel

2

4.3

75

5

Sino-implant(II)®

Levonorgestrel

2

4

75

4

aIn the UK, Implanon NXT® is marketed as Nexplanon® and will be referred to thus hereafter

The two rod levonorgestrel implants should be inserted in a v-shape with a 30 degree arc. The rate at which etonogestrel is released into the circulation from the implant decreases with time. In the first 5–6 weeks the release rate is approximately 60–70 μg/day: by the end of year 3 it is approximately 25–30 μg/day (Merck Sharp & Dohme Limited 2013). The release rate of levonorgestrel steadily decreases over time up until year three and then remains relatively steady in years four and five (Sivin et al. 2002).

Implanon® and Nexplanon® are bioequivalent (Schnabel et al. 2012): the main differences between the two products are their inserters and the addition of barium sulfate to Nexplanon®, which makes it radiopaque. The two rod levonorgestrel implants contain the same dose of levonorgestrel, however, the Sino-implant (II) is licensed for a shorter duration of use.

Progestogen-only implants provide contraceptive protection via a variety of mechanisms; ovulation suppression, thickening of cervical mucus and possibly endometrial changes (Croxatto 2002). The extent to which ovulation is suppressed varies between the implants, with it more consistently suppressed for up to 3 years in those who use the etonogestrel implant (Croxatto 2002). For Implanon® and Nexplanon®, the effects of the etonogestrel on cervical mucus and endometrium are therefore perhaps of less clinical importance than for levonorgestrel implants.

Efficacy and Unintended Pregnancies

Data from clinical trials suggest that progestogen-only implants are highly effective methods of contraception with a Cochrane review quoting pregnancy rates of 0.13 and 0 per 100 women for the levonorgestrel and etonogestrel implants respectively (Power et al. 2007). The probability of pregnancy in the first year of Sino-implant (II) use has been reported as being up to 0.1 % and cumulatively up to 2.1 % at 5 years (Steiner et al. 2010). It is therefore rare for etonogestrel or levonorgestrel implants to truly ‘fail’. That said, cases of unintended pregnancy with contraceptive implants in situ have been reported and it is likely that pregnancy rates from trials under-represent the number of failures that will occur in real life when external factors such as insertion difficulties and drug interactions come into play.

In 2005 a case series (Harrison-Woolrych and Hill 2005) from Australia was published following reports of unintended pregnancies arising with use of the etonogestrel implant. While not a direct failing of the implant itself, unrecognised non-insertion of the implant led to a number of unintended pregnancies. This will be covered later in this chapter. Additionally, this case series identified that a number of failures occurred as a result of concomitant use of enzyme inducing drugs (Harrison-Woolrych and Hill 2005). Other reports of failures possibly as a consequence of drug interactions are documented (Patni et al. 2006; Lakhi and Govind 2010; McCarty et al. 2011; Matiluko et al. 2007; Haukkamaa 1986; Gbolade 2010): product information warns that efficacy may be reduced with concomitant use of drugs which induce hepatic enzymes, specifically cytochrome P450, for example carbamazepine or rifampacin (Merck Sharp and Dohme Limited 2013). In 2014, the Medicines and Healthcare Regulatory Agency (MHRA) in the UK produced a Drug Safety Update (Medicines and Healthcare Products Regulatory Agency 2014) which highlighted that in the last quarter of 2013 the MHRA had received two reports of unintended pregnancies occurring in women using the etonogestrel implant possibly as a consequence of using St John’s Wort.

It is recommended that women using enzyme inducing drugs concomitantly with the etonogestrel implant should switch to a method such as a copper intrauterine device (Cu-IUD) whose efficacy is considered to be unaffected by these medicines (Faculty of Sexual and Reproductive Healthcare 2011a). Alternatively, a short-term option would be to use an additional contraceptive method, for example condoms, while taking the enzyme-inducing drugs and for 28 days afterwards (Faculty of Sexual and Reproductive Healthcare 2011a).

In the UK, by November 2013, the MHRA had approximately 1,344 pregnancies on file for Implanon®, 1,076 of which are listed specifically under the heading Unintended Pregnancies (Medicines and Healthcare Products Regulatory Agency 2013). In 2011, a Danish Pharmacovigilance Update suggested 28 cases of unintended pregnancy in women using the etonogestrel implant had been reported since its introduction in 1999 (Danish Medicines Agency 2011).

As a result of reported cases of non-insertion, clinicians have placed emphasis on palpation of the rod in the arm after insertion by both clinician and patient. Despite this, cases continue to occur, some resulting in litigation. Additional training has been shown not to be the answer to problems relating to human factors; applicator design is likely to be a more fruitful approach to risk management (Rowlands et al. 2010).

In the UK, the Faculty of Sexual and Reproductive Healthcare (FSRH) advises the removal of the implant should pregnancy occur with an implant in situ, unless the woman is going to have a termination and wants to continue the method afterwards (Faculty of Sexual and Reproductive Healthcare 2014).

Pregnancies documented with an implant in situ may also arise from an implant being inserted around the time of conception or from a woman not adhering to any stipulated requirements for additional precautions when starting the method.

Weight and Body Mass Index (BMI) Issues for Progestogen-Only Implants

Studies have found an inverse relationship between hormone concentrations and weight, or BMI, which has caused concern that contraceptive implants may be less effective or effective for a shorter duration of time for women who are classified as obese, than for women of ‘normal’ weight/BMI. A pharmacokinetic study (Mornar et al. 2012) found that in the first 6 months following insertion of Implanon®, women classified as obese, had plasma levels of etonogestrel up to 63 % lower than levels reported for normal weight women, although the difference was not statistically significant. The authors noted that the findings may be subject to confounding as a result of racial differences between the two groups (obese and normal weight) (Mornar et al. 2012).

A small case series (Ciangura et al. 2012) of three morbidly obese women (BMI 49.2–64.7 kg/m2) undergoing bariatric surgery similarly reported serum etonogestrel levels far lower than might be expected in women of normal weight. The authors indicated the need for further research, but suggested that in obese women undergoing bariatric surgery, levels of etonogestrel sufficient to suppress ovulation may only be present for up to 8 months (Ciangura et al. 2012). Such findings (and from only three women), however, do not necessarily confirm a reduced contraceptive effect as, even if reduced plasma levels resulted in less ovarian suppression, the secondary effects of the implant may still offer sufficient contraceptive protection.

In terms of calculating failure rates according to body weight or BMI, the data are quite limited. With a growing epidemic of obesity in many countries, more studies are required as clinical trials to date have often failed to include women weighing more than 130 % of their ideal body weight and few trials have included women weighing over 100 kg for the full duration of implant use.

In two studies of the levonorgestrel implant, pregnancies were reported in women weighing over 70 kg at the time of their levonorgestrel implant insertion: 131/1198 (Sivin et al. 1998b) and 134/511 (Sivin et al. 1998a) women weighed 70 kg or over at baseline. In the smaller study (Sivin et al. 1998a) of 511 women, pregnancies occurred in women weighing over 79 kg. A cumulative failure rate at five years of 4.2 per 100 women was calculated for women weighing over 70kg (Sivin et al. 1998a). Product information for Jadelle® suggests that women over 60 kg may wish to consider replacing the device at 4 years (New Zealand Consumer Medicine Information 2013a). In a large cohort study in which implant (etonogestrel) users who were overweight or obese were compared to women of ‘normal’ weight and to women using intrauterine devices, no reduction in efficacy was observed with the implant as a result of high body mass index (Xu et al. 2012).

Longer Term Risks and Benefits

As indicated in Chaps. 5 and 6, few long-term epidemiological studies have included sufficient numbers of women using progestogen-only methods to be able to reach definitive conclusions about the associated risks or benefits in relation to cardiovascular health, cerebrovascular disease and cancer. Data for progestogen-only implants in particular are lacking. The available evidence for other progestogen-only methods generally suggests no increased risk of thrombosis, myocardial infarction (MI) or stroke (Lidegaard et al. 2012ab; Mantha et al. 2012; Chakhtoura et al. 2011). For women with multiple risk factors for cardiovascular disease, published medical eligibility criteria for contraceptive use indicate that the benefits of using progestogen-only implants generally outweigh any risks (Faculty of Sexual and Reproductive Healthcare 2009a; Centre for Disease Control and Prevention 2010; World Health Organization 2010). The risk of breast cancer associated with use of the progestogen-only implant is undetermined due to small sample sizes in studies that have examined this, but no increased risk has been observed (Strom et al. 2004).

Non-contraceptive Benefits of Progestogen-Only Implants

As primary dysmenorrhoea is associated with menstruation, contraceptive devices that suppress ovulation may be expected to alleviate ovulatory pain. An integrated analysis (Mansour et al. 2008a) of bleeding patterns from eleven clinical trials of the etonogestrel implant noted that five of these trials reported on dysmenorrhoea. At the time of removal, dysmenorrhoea was noted to have improved in 77 % of those who reported it at baseline (Mansour et al. 2008a). For some women however, dysmenorrhoea may occur or worsen with use of the etonogestrel implant (Croxatto 2000; Mansour et al. 2008a).

European Guidelines (European Society for Human Reproduction and Embryology 2013), advise that the levonorgestrel intrauterine system (LNG-IUS), the progestogen-only injectable (depot medroxyprogesterone acetate) and combined oral contraceptives can be considered for the management of dysmenorrhoea secondary to endometriosis. Few studies have looked at the use of the progestogen-only implant in managing dysmenorrhoea secondary to pelvic pathology but there is some data to suggest a possible benefit (Walch et al. 2009; Yisa et al. 2005; Ponpuckdee and Taneepanichskul 2005). In a pilot study of 41 women with histologically confirmed endometriosis randomised to either the progestogen-only implant or the progestogen-only injectable (depot medroxyprogesterone acetate), endometriosis associated pain was reduced in both groups and their therapeutic effects comparable (Walch et al. 2009). However, the etonogestrel implant is not currently listed in European guidelines as a suggested treatment strategy (European Society for Human Reproduction and Embryology 2013).

Other Risks

Bent/Fractured Implants

Although reports of bent and/or fractured implants are uncommon in the literature, there are several examples of case reports and health professional correspondence detailing experiences of this phenomenon in relation to the etonogestrel implant (Doshi 2011; Bentley 2013; Torres et al. 2013; Pickard and Bacon 2002; Agrawal and Robinson 2003). Although details of the specifics are not documented, a total of 149 cases of broken devices, 11 damaged devices and 5 device kinks are listed in UK reporting systems for the etonogestrel implant (Medicines and Healthcare Products Regulatory Agency 2013). The implications of implant fractures in terms of efficacy are largely unknown: correspondence from Rekers reports that a damaged etonogestrel implant is unlikely to affect contraceptive efficacy of these single rod implants as, compared to those that are undamaged, the in vitro release rate is only slightly increased (Rekers 2013). No cases of bent or fractured Jadelle® implants are on file with the licence holder (personal communication).

Bone Health

It is well recognised that use of the progestogen-only injectable is associated with a reduction in bone mineral density (BMD) which usually recovers upon cessation (Faculty of Sexual and Reproductive Healthcare 2008; National Institute for Health and Care Excellence 2005; Lopez et al. 2012). Less is known about the impact of the progestogen-only implant, but it is suggested that on the basis of the available evidence there is not thought to be a clinically significant adverse effect (Faculty of Sexual and Reproductive Healthcare 2014).

Beerthuizen et al. (2000) compared users of the etonogestrel implant to users of a non-hormonal intrauterine device over a 2 year period to study the effects of the implant on bone mineral density. From baseline, the observed changes in the implant group were reported not to be different to those experienced by intrauterine device users (Beerthuizen et al. 2000). However, in other observational studies, a statistically significant loss of bone mineral density compared to pre-insertion values was observed in the distal radius, but not the ultra-distal radius, in the small number of etonogestrel and levonorgestrel implant users who continued their method for up to 36 months (Monteiro-Dantas et al. 2007); losses were also observed after 18 months of use (Bahamondes et al. 2006a). A cross-sectional study reported statistically significant changes in bone mineral density in the ulna and distal radius in women using the etonogestrel implant compared to women using non-hormonal contraceptives (Pongsatha et al. 2010).

In summary, although studies of progestogen-only implants have noted some statistically significant decreases in bone mineral density (Beerthuizen et al. 2000; Monteiro-Dantas et al. 2007; Bahamondes et al. 2006a; Pongsatha et al. 2010) the decreases may not be of clinical significance as bone mineral density is only a surrogate endpoint for fractures. As yet, the risk of fractures associated with progestogen-only implants is undetermined.

Ectopic Pregnancy

The fact that progestogen-only implants are such effective methods of contraception means that the absolute risk of pregnancy, ectopic or intrauterine, is low. Post-marketing surveillance of Norplant® reported an ectopic pregnancy rate of 0.30 per 1,000 woman years of use in women using Norplant® compared with 2.66 per 1000 woman years amongst those not using any contraception (International Collaborative Post-Marketing Surveillance of Norplant 2006). Other studies have similarly reported low ectopic pregnancy rates for Norplant® and Jadelle® (Sivin et al. 1998b).

However, when a pregnancy does occur while using a progestogen-only implant, it may be more likely to be ectopic. In post-marketing surveillance, around 11 % of those pregnancies that occurred when using Norplant® were ectopic compared with 0.6 % of women using no method (International Collaborative Post-Marketing Surveillance of Norplant 2006). A published review of clinical trials and marketing data suggested that ectopic pregnancies accounted for around 5 % of all reported pregnancies whilst using Implanon® (Graesslin and Korver 2008). Case reports of ectopic pregnancy have also been documented following concomitant use of drugs that may affect the efficacy of progestogen-only implants such as anti-retrovirals (Patni et al. 2006; McCarty et al. 2011). In the UK, there are 57 ectopic pregnancies on file which could relate to use of the etonogestrel implant (Medicines and Healthcare Products Regulatory Agency 2013). If a pregnancy does occur with a progestogen-only implant in situ, the possibility of an ectopic pregnancy should be considered.

Expulsion

Spontaneous expulsion of an implant after correct insertion is close to impossible (Fraser 2006). A review of clinical trials on all types of implant gave an expulsion rate of between 0 and 0.6 % (Brache et al. 2002). Expulsions were reported to occur within the first 4 months after insertion in 70 % of cases (Brache et al. 2002). Implanon® trials showed an expulsion rate of zero (Mascarenhas 1998). However, there are several post-marketing case reports of expulsion/extrusion of Implanon®/Implanon NXT® (Gwinnell 2007; Chaudry 2013; Mansour 2013). It appears to be a slow process of erosion culminating in partial expulsion.

Discontinuation rates due to implant expulsions are low (Division of Human Resource Development Research1993) and in a case series expulsions accounted for only 3/218 unintended pregnancies with Implanon® use (Harrison-Woolrych and Hill 2005). Sixteen cases of expulsion/extrusion are on file in the UK in relation to the etonogestrel implant (Medicines and Healthcare Products Regulatory Agency 2013): it is not possible however to determine whether these are actual expulsions or whether non-insertion may account for some of these.

Infection/Implant Site Reactions

Implant site reactions, pain and infection have been noted in clinical trials of implantable contraceptives (Klavon and Grubb 1990; Dunson et al. 1995). In a review of Implanon® trials, swelling at the insertion site occurred in 0.5 % of insertions, redness in 0.3 % and pain in 1.9 % of cases (Mascarenhas 1998). A study of Nexplanon® showed an incidence of swelling or redness of 4.7 % (Mansour et al. 2010). Post-insertion wound infection is not reported in trials of Implanon®/Nexplanon®.

A case of lipoatrophy around the site of Implanon® insertion was reported in a 40 year old woman, which resolved 6 months after removal (Lindsay 2010). A response from Schering Plough Ltd, indicated that whilst a relationship between the implant and the lipoatrophy was possible, there was insufficient evidence to establish causality and that other possible factors may have played a role (Mohlala and Falowo 2010). A case of lipoatrophy has also been reported in a young woman who presented for removal of her Norplant device (Chadha-Gupta and Moss 2007). In the UK at the end of 2013, two reports of lipoatrophy were listed on the drug analysis print for the etonogestrel implant (Medicines and Healthcare Products Regulatory Agency 2013).

Insertion and Removal Difficulties: Non and Deep Insertion and Nerve Damage

Whilst it is important to understand the benefits and risks associated with the use of progestogen-only implants, there are a number of safety issues relating to the device itself and the procedures required to be undertaken to insert or remove the device. Harm/risk related to the insertion and removal of contraceptive implants can generally be divided into three categories: non-insertion, deep insertion and nerve injury (Rowlands 2010a).

The risk of non-insertion is of course that a woman leaves the clinical setting without a reliable contraceptive method in situ and is therefore at increased risk of an unintended pregnancy and the potential negative consequences this may have for her. Failings, due to human factors (Dekker 2011), leave clinicians open to the possibility of litigation (Rowlands 2010a). During the first 3 years of marketing of the etonogestrel implant in Australia, over 200 unintended pregnancies were reported (Harrison-Woolrych and Hill 2005). Of the 127 cases, after excluding those who were deemed to be pregnant at the time of insertion and those for whom there was insufficient information to deduce a reason, 66 % (n = 84) were attributed to failed insertions (Harrison-Woolrych and Hill 2005). Similarly in France, around 30/77 unintended pregnancies over a 17 month period were considered to be the result of an insertion technique error (Bensouda-Grimaldi et al. 2005).

In the UK, the Medical Defence Union (MDU) published advice to general practitioners (GPs) inserting contraceptive implants in 2011 indicating that the organisation had been notified of 29 claims in relation to use of the etonogestrel implant: most related to pregnancy failure and concerns about insertion failings (MDU 2011). An overview of legal implications of contraceptive implants, including further examples of litigation, has been published (Rowlands 2010a).

A new inserter has been developed with Nexplanon® in part to eliminate the risk of insertion errors. The risk of non-insertion may be less with implants such as the Sino-implant (II), that require to be manually inserted into a trocar, as the health professional has to observe the implant throughout the insertion process (Rowlands et al. 2010). In their article assessing the risks associated with the insertion and removal of contraceptive implants, Rowlands et al. (2010) postulate that, as it is highly unlikely the preloaded applicator systems have been supplied with an absent implant, the problems with Implanon® non-insertion are generally a result of human factors: most likely that the applicator is removed with the implant still in situ. Palpating the arm to check for the implant(s) and documenting the implant’s presence has been proposed as a way of minimising the possibility of an unidentified non-insertion.

In terms of siting an implant, the arm has the advantage over other sites, in that the subcutaneous tissue is thinner thereby easing the insertion process: the disadvantage is that vital structures are nearer the surface (Rowlands et al. 2010). Progestogen-only implants are licensed for insertion in the sub-dermal plane; however there are several reports in the literature of impalpable implants which upon further investigation are found to be located far deeper than expected, which can present health professionals with difficulties at the time of removal (Singh et al. 2006). In a single centre in France, a retrospective case series identified 28 women for whom their etonogestrel implant had to be removed in an operating theatre: over a third of women (11/28) were found to have an implant deep to the fascia; one had to retain her implant as it could not be located, and three were found near or touching the brachial artery (Vidin et al. 2007).

Following correct insertion of a contraceptive implant, significant migration appears to be a relatively uncommon occurrence: of 87 women followed prospectively for 1 year, migration did not occur in 45 % of these women (Ismail et al. 2006). In the remaining 55 % for whom some degree of migration occurred, migration was predominantly caudally, and in all but one case, migration was less than 2 cm- no deep implant migration was noted (Ismail et al. 2006). The view, certainly in the case of Implanon®, would seem to be that deep insertions are more likely to be the result of poor insertion technique (Rowlands et al. 2010; Singh et al. 2006; Walling 2005).

Weight may play a role in difficult insertions and removals. It has been suggested that where women have scant subcutaneous tissue, deep insertion may be more likely to occur (Mansour et al. 2008b) and that weight gain following insertion may make palpation difficult (Navani and Robinson 2005). Whereas other devices are not visible on X-ray, the addition of 15 mg of barium sulfate means that a non-palpable Nexplanon® could be located via X-ray or computed tomography scan, although visualisation via ultrasound should still be the first course of action. Removal problems with Jadelle® (Norplant II) occur less often than with Norplant® (Sivin et al. 1998b). In New Zealand, up until June 2013, 21 reports of location or removal difficulties with Jadelle and three reports with Implanon® were on file with the Centre for Adverse Reactions Monitoring (New Zealand Medicines and Medical Devices Safety Authority (2013b)).

With incorrect insertion and impalpable implants, the potential arises for the third type of harm – nerve injury. In 2012, a case was reported in which an impalpable Implanon® was located on the deep surface of the fascia beside the medial cutaneous nerve of the forearm (Brown and Britton 2012). The woman had been experiencing forearm pain and hypoesthesia for 2 years following insertion of Implanon®, which subsequently resolved after removal (Brown and Britton 2012). In 2011, two cases of median nerve injury were reported (one a 10 % laceration, the other an incomplete but significant high median nerve injury), arising from exploratory procedures to locate an impalpable Implanon® (Gillies et al. 2011). The authors (Gillies et al. 2011) noted that both cases were potentially preventable, had the clinician followed advice to image impalpable implants prior to attempting removal. Other reports of medial cutaneous nerve damage can be found, as can cases of ulnar nerve damage, ulnar lesions and contusion following removal of progestogen-only implants (New Zealand Medicines and Medical Devices Safety Authority 2013b; Bragg et al. 2006; Osman et al. 2005). Two cases of possible compression of the musculocutaneous nerve with Norplant® have been reported (Hueston and Locke 1995).

Table 8.2 highlights the number of adverse reactions reported to the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) (Medicines and Healthcare Products Regulatory Agency 2013) relating to etonogestrel implants (during the period Nov 1999– Nov 2013) which may possibly be as a result of nerve damage. While they cannot be used to predict the frequency of such events occurring, these reports would seem to reflect the types of case reports available in the published literature.

Table 8.2

Neurological adverse events from UK spontaneous reporting, 1999–2013 for etonogestrel single agent products

Adverse reaction

Number of cases reported

Implant site paraesthesia

3

Nerve injury (not classified)

1

Peripheral nerve injuries

7

Paraesthesias and dysaesthesias

42

Mononeuropathies

2

Sensory abnormalities

31

Vascular Injury

Injuries to vascular structures are extremely rare. In a French case, an Implanon® was inserted into the brachial artery causing thrombus formation (Mourtialon et al. 2008). In a German case, an Implanon® was inserted and then was not palpable (Ernst 2004). Ultrasound and magnetic resonance imaging (MRI) failed to locate the rod; MRI scanning was extended to the heart. Echocardiography of the heart, pulmonary artery angiography and phlebography of lung veins and superior vena cava were also done and did not locate the implant. Quantitative blood etonogestrel levels were positive confirming the implant was in the body. A cardiothoracic specialist concluded that the implant might be lodged in a branch of the pulmonary artery, possibly up to a peripheral branch of a lung segment and that it was unlikely to cause serious problems. The assumption was that the implant had embolised in the venous circulation from a vein in the arm.

Avoidance of Injury

Placing the implant superficially, away from the neurovascular bundle in the upper arm is important in minimising risk of injury to vital structures. Clinicians inserting and removing implants should receive training approved in their country. Skills should be maintained with regular updating.

Sometimes implants are impalpable; these deeply located implants are more complex to remove. Ultrasound-guided removal is recommended which should only be performed by clinicians with particular expertise.

Side Effects of Progestogen-Only Implants

Bleeding Disturbances

A change in bleeding pattern is a common side effect associated with the use of progestogen-only implants, and often a stated reason for dissatisfaction with and/or discontinuation of these methods (Sivin et al. 1998b; Mansour et al. 2008a; Harvey et al. 2009; Lakha and Glasier 2006; Funk et al. 2005; Darney et al. 2009; Grunloh et al. 2013; Zheng et al. 1999; Short et al. 2014). Bleeding patterns are broadly similar for all progestogen-only implants, although less frequent bleeding and a higher incidence of amenorrhoea have been noted amongst Implanon® users compared to Norplant® users (Zheng et al. 1999). Irregularity is the most commonly experienced bleeding pattern with contraceptive implants, with bleeding that is frequent and/or prolonged appearing to be the most unacceptable to women (Mansour et al. 2008a; Biswas et al. 1996). A review of bleeding patterns from 11 trials of Implanon® suggested that while bleeding patterns may improve amongst those who find the bleeding unfavourable in the first few months of use, for others the bleeding patterns are likely to remain unacceptable (Mansour et al. 2008a).

A variety of interventions such as administration of antiprogestogen, estrogen supplementation and additional progestogen have been tried to improve the bleeding patterns associated with progestogen-only methods and may offer short-term benefits, but evidence to support routine use of any of these interventions or use in the longer term is lacking (Abdel-Aleem et al. 2013a).

Breast Pain/Acne/Weight Gain and Headaches

Breast pain has been reported by around 10 % of women in clinical trials of progestogen-only implants, although it accounted for less than 1 % of women who discontinued the method for this reason (Darney et al. 2009).

Acne has been reported by women as a side effect of implant use (Darney et al. 2009; Yildizbas et al. 2007; Flores et al. 2005). Product information for the etonogestrel implant indicates that acne was a very commonly (>1/10 women) reported undesirable effect in clinical trials and it is cited as a reason for method discontinuation (Sivin et al. 1998b; Darney et al. 2009; Grunloh et al. 2013; Urbancsek 1998). As with bleeding, it is difficult to predict what will occur in an individual woman.

In clinical trials, women have reported weight gain as a reason for discontinuing progestogen-only implants (Funk et al. 2005; Urbancsek 1998). A 5-year trial of Jadelle reported that amongst those who continued to use the method, the average weight gain per year was 0.7 kg (Sivin et al. 1998b). However, there were variations with some women losing weight and others gaining much more within the first year of use. It has been reported that compared with users of the non-hormonal copper intrauterine device, etonogestrel implant users are more likely to report perceived weight gain (Nault et al. 2013).

Because the progestogen-only implant is not thought to be associated with an increased risk of stroke, medical eligibility criteria generally support initiating progestogen-only implants in women with migraine, including migraine with aura (Faculty of Sexual and Reproductive Healthcare 2009a; Centre for Disease Control and Prevention 2010; World Health Organization 2010). However, headaches are a commonly reported side effect in trials of progestogen-only implants and a reason for method discontinuation – although there is little available evidence investigating the role of progestogen-only contraceptives in headache development and a causal relationship has not been established (Faculty of Sexual and Reproductive Healthcare 2014; National Institute for Health and Care Excellence 2005). An integrated analysis of 11 clinical trials reported that headache was a side effect reported by 5 % or more of subjects with around 1.6 % of women discontinuing their method due to headaches (Darney et al. 2009). In another study, 7.5 % of women who asked to stop their etonogestrel implant early did so because of headaches (Grunloh et al. 2013).

Hair Loss

One of the possibly related undesirable side effects noted within the product licensing information of levonorgestrel and etonogestrel implants is hair loss/alopecia: the Summary of Product Characteristics (SPC) for the etonogestrel implant suggests it has been reported in 1–10 % of women in clinical trials (Merck Sharpe and Dohme Limited 2013). The MHRA (Medicines and Healthcare Products Regulatory Agency 2013) in the UK, has 66 reports of alopecia/alopecia areata/alopecia totalis listed in its drug analysis prints for the etonogestrel implant. A study investigating continuation rates of LARCs and characteristics of those discontinuing, reported that 3.2 % (3/94) of women who stopped the etonogestrel implant before 6 months of use did so because of hair loss (Grunloh et al. 2013). Despite these reports, evidence confirming an association is lacking and further research is needed.

Reduced Sexual Interest

Decreased libido is again commonly noted (>1 % <10 %) as a possibly related undesirable effect of progestogen implant use. As mentioned in Chap. 5 in relation to oral contraceptives, establishing causality is difficult given the many other factors that could influence sexual interest and there is a lack of studies investigating this. Di Carlo et al. (2014) conducted a preliminary study into the impact of Nexplanon® on sexual function and quality of life via validated questionnaires in a small group of healthy Italian women and did not find any adverse effects (Di Carlo et al. 2014).

Ovarian Cysts

It is not uncommon for women using progestogen-only implants to have persistent ovarian follicles or cysts and these become more common with increasing duration of use (Hidalgo et al. 2006). Ovarian cysts have been reported to occur more frequently amongst users of progestogen-only implants than amongst users of a copper intrauterine device (Cu-IUD) (Hidalgo et al. 2006). Treatment of ovarian cysts in progestogen-only implant users is not usually required and spontaneous resolution is common (Hidalgo et al. 2006).

Return of Fertility After Use of Progestogen-Only Implants

Women may be concerned about the impact long-acting methods of contraception have on their future fertility. Cumulative conception rates of 80.3 per 100 women at 1 year and 88.3 % per 100 women at 2 years have been documented in women stopping Jadelle® for the purposes of pregnancy planning (Buckshee et al. 1995). Within 1 month of discontinuation, 20 % of women had conceived and duration of use did not appear to be a factor in return of fertility when comparing 2 or more years of use to less than 2 years of use (Buckshee et al. 1995). Those over the age of 30 took on average 6 months to become pregnant following stopping for the purposes of pregnancy, versus 3.8 months for those under the age of 30 (Buckshee et al. 1995). Similar pregnancy rates at 12 months have been noted in other studies for Norplant® and Jadelle® (Diaz et al. 1987; Sivin et al. 1992).

Following removal of the etonogestrel implant, ovulation returns quickly. In one study approximately 91 % of women reported return of ‘normal’ menses within 3 months of the implant being removed and of those who reported non-use of contraception (pregnancy intentions unknown), around 14 % had become pregnant within 90 days (Croxatto et al. 1999). Similar findings were reported by Funk et al. (2005) who noted that of the 282 women who were evaluated 3 months after their Implanon® was removed, 88 % reported that their normal menses had resumed: nearly a quarter (11/46) of women who did not use any subsequent contraception became pregnant between 7 and 131 days following removal. Guidance in the UK suggests women be informed that there is no evidence of a delay in return to fertility (National Institute for Health and Care Excellence 2014) and that effective contraceptives are required following removal, if a woman wishes to avoid an unintended pregnancy (Faculty of Sexual and Reproductive Healthcare 2014).

Section Summary: Progestogen-Only Implants

Progestogen-only implants are highly effective, long-acting, reversible methods of contraception. Women commonly experience irregular bleeding with use of these methods – often resulting in discontinuation. Unfortunately, there is little evidence for how best to treat such events long-term.

Adverse events such as stroke, MI or venous thromboembolism (VTE) are not thought to be associated with use of contraceptive implants and although data on use are lacking in high risk groups, progestogen-only implants are generally considered a highly effective option for women with risk factors or a history of these conditions.

While there is little evidence in terms of breast cancer risk, as with other progestogen-only methods, any observed increased risk with use is likely to be small. However, use in women with current breast cancer is not advised.

With use of contraceptive implants, many of the risks experienced are not a result of the implant itself, rather as a consequence of human factors associated with insertion and removal of the device and therefore there is scope for such risks to be reduced.

Intrauterine Devices

Before the development of oral contraceptives, contraceptive implants and injectables, women’s contraceptive options were limited to barrier methods such as condoms and diaphragms, and to non-hormonal intrauterine devices. The non-hormonal intrauterine devices have been available in many forms and some such as the Dalkon Shield have been subject to much controversy (Sivin 1993). Modern day intrauterine methods are classified as non-hormonal or hormonal.

Copper-intrauterine devices (Cu-IUDs) are non-hormonal devices which were introduced onto the market in the late 1960s. The copper content varies between the different types and sizes available but they are mostly T-Shaped devices. An intrauterine ball (IUB) is currently under investigation: the IUB takes on a 3-dimensional spherical form (Baram et al. 2014), whereas the currently marketed devices take on a 2-dimensional shape in the uterus.

In the UK and some other countries such as the US, the currently available hormonal intrauterine devices contain either 52 mg of levonorgestrel (LNG-IUSs) (Mirena®, Levonova®) or 13.5 mg of levonorgestrel (Jaydess®, Skyla®), hereafter referred to as LNG-IUS and 13.5 mg LNG-IUS respectively. The daily release rate for the LNG-IUS is 20 μg (Bayer PLC 2013); for the 13.5 mg LNG-IUS release starts at 14 μg/day reducing to 5 μg/day at 3 years (Bayer PLC 2014). The 13.5 mg LNG-IUS can be distinguished from the LNG-IUS by the presence of a silver ring just below the side arms which shows up on both X-ray and ultrasound scan (see diagram below).

A318199_1_En_8_Figa_HTML.gif

Whereas the LNG-IUS is licensed for contraceptive cover for 5 years, the 13.5 mg LNG-IUS is only licensed for 3 years. The 13.5 mg LNG-IUS is currently only licensed for contraception (Bayer PLC 2014) and not for the treatment of heavy menstrual bleeding or indeed endometrial protection, which, in the UK, the LNG-IUS is (Bayer PLC 2013).

Effectiveness of IUDs

The contraceptive effect of intrauterine contraceptives is achieved via a variety of mechanisms. While endometrial changes that occur with use of both hormonal and non-hormonal intrauterine devices are likely to have an effect on implantation, the primary mechanism of action for both methods is interference with the process of fertilisation (Ortiz and Croxatto 2007).

Cu-IUDs and LNG-IUSs are highly effective methods of contraception with very low failure rates; over 5 years less than 20 in 1,000 and 10 in 1,000 unintended pregnancies respectively would be expected (National Institute for Health and Care Excellence 2005). While pregnancy with one of these methods in situ is rare, there is a greater risk of an adverse pregnancy outcome (e.g. ectopic pregnancy or preterm delivery) if a pregnancy does occur with an IUD in situ. This risk may not be completely negated by early removal of the device but appears to offer more favourable outcomes than retention (Brahmi et al. 2012).

Cu-IUDs, depending on their copper content, are recommended for use for between 5 and 10 years. Studies have demonstrated their efficacy beyond this and in some countries, for example in the UK, the FSRH advises that a Cu-IUD, providing it has a copper load of over 300 mm2, may be able to be used for longer than 10 years, on the proviso that the woman is over the age of 40 at the time the device is inserted (Faculty of Sexual and Reproductive Healthcare 2010). At 7 years, the cumulative pregnancy rates with a LNG-IUS in situ are only slightly higher than at 5 years (up to 1.1 and up to 1 per 100 women years respectively (Diaz et al. 1993; Cox et al. 2002; Sivin et al. 1991; Andersson et al. 1994; Nilsson et al. 1983), although some studies (Diaz et al. 1993; Sivin et al. 1991) may have included devices containing more levonorgestrel than in the currently marketed device. However, in the UK, it is recommended that if a woman is over the age of 45 she can consider using the LNG-IUS for longer than 5 years for contraceptive purposes (National Institute for Health and Care Excellence 2005; Faculty of Sexual and Reproductive Healthcare 2010). For the 13.5 mg LNG-IUS, the reported cumulative contraceptive failure rate from an randomised controlled trial (RCT) conducted over 3 years was 0.9 % (Nelson et al. 2013).

As it is a non-hormonal method, the efficacy of the Cu-IUD would not be expected to be affected by concomitant drug use. A report (Zerner et al. 1981) in which pregnancies were documented in Cu-IUD users, using concomitant immunosuppressive drugs led to concerns about reduced efficacy when using these types of medications. There is however no evidence from large studies to substantiate an effect. Product information for the LNG-IUS suggests that its efficacy in the presence of enzyme inducing drugs has not been studied, but is not thought to be a concern due to its predominantely local mechanisms of action (Bayer PLC 20132014). A small observational series noted low failure rate when the LNG-IUS was used with enzyme inducing drugs (Bounds and Guillebaud 2002): the authors indicated that if any increased risk of pregnancy existed, it would be considered to fall within acceptable limits and the LNG-IUS was therefore an appropriate option for women using such drugs (Bounds and Guillebaud 2002). Women using enzyme inducing drugs, who are using other forms of contraception, may be advised to switch to an intrauterine method (Faculty of Sexual and Reproductive Healthcare 2011a).

Benefits of Intrauterine Devices

Reduced Dysmenorrhoea

Women with primary or secondary dysmenorrhoea may benefit from use of the LNG-IUS (Faculty of Sexual and Reproductive Healthcare 2015; Bounds and Guillebaud 2002). Dysmenorrhoea and bleeding have been shown to be significantly reduced with use of the LNG-IUS compared with use of a Cu-IUD (Nilsson et al. 1982) and that severity of dysmenorrhoea may also be improved (Lindh and Milsom 2013; Kelekci et al. 2012; Nilsson et al. 1982). Pain/cramping have however been reported as reasons for discontinuation of both methods. In one large cohort study, analysis of reasons for method discontinuation showed that around 28 % of LNG-IUS discontinuers and 35 % of Cu-IUD discontinuers reported that pain/cramping was their primary reason for having requested removal before 6 months of use (Grunloh et al. 2013).

Dysmenorrhoea secondary to endometriosis or adenomyosis has been shown to be reduced with use of the LNG-IUS (Tanmahasamut et al. 2012; Lockhat et al. 2005; Crosignani et al. 1997; Petta et al. 2005; Tekin et al. 2011; Cho et al. 2008; Sheng et al. 2009; Fedele et al. 1997; Ozdegirmenci et al. 2011) and is a recommended treatment option (European Society for Human Reproduction and Embryology 2013). The LNG-IUS may also help in reducing the recurrence of dysmenorrhoea following surgical interventions for endometriosis (Abou-Setta et al. 2006).

Endometrial Protection

One of the licensed indications of the LNG-IUS in the UK is protection from endometrial hyperplasia during estrogen replacement therapy (Bayer PLC 2013). A systematic review reported that compared with oral and vaginal administration of progestogen, in women using estrogen replacement therapy, the LNG-IUS is at least as effective in preventing endometrial proliferation and consequentially endometrial pathology (Wan and Holland 2011).

Studies have also sought to investigate its role in the treatment of endometrial hyperplasia. The findings are somewhat limited by a lack of randomised controlled trials (RCTs). A systematic review and meta-analysis of observational studies suggested that the LNG-IUS was no more or less effective than oral progestogens at inducing simple hyperplasia disease regression compared to oral progestogens, but would appear to induce disease regression at a higher rate for both complex hyperplasia (pooled rate of 92 vs 66 % respectively p < 0.01) and for atypical hyperplasia (90 vs 69 %; p = 0.03) (Gallos et al. 2010). A subsequently published comparative cohort study of 344 women with non-atypical complex hyperplasia or with atypical hyperplasia, similarly reported more favourable outcomes with treatment of the LNG-IUS compared with oral progestogens (Gallos et al. 2013).

A systematic review of RCTs, however, concluded that for both non-atypical and atypical hyperplasia the evidence is insufficient to recommend the LNG-IUS as an equivalent treatment to high dose progestogens or hysterectomy (Wan and Holland 2011) and a Cochrane review concluded that more randomised controlled trials are required to establish the efficacy of the LNG-IUS in the treatment of women with atypical hyperplasia (Luo et al. 2013). For women using tamoxifen, use of an LNG-IUS may also help to reduce the formation of endometrial polyps and hyperplasia (Wan and Holland 2011; Chin et al. 2009).

Whilst a non-hormonal device, use of a Cu-IUD has been associated with a reduced risk of endometrial cancer (Hubacher and Grimes 2002; Beining et al. 2008) and cervical cancer (Castellsague et al. 2011). One theory on the cause of these protective effects is that the chronic low-grade inflammatory response to Cu-IUDs results in reduced mitotic activity and reduced oestrogen receptor concentrations.

Reduced Bleeding

The LNG-IUS is licensed for contraception and/or treatment of heavy menstrual bleeding (Bayer PLC 2013) and a recommended treatment option (National Institute for Health and Care Excellence 2007). The effectiveness of the LNG-IUS in reducing menstrual blood loss as a treatment of heavy menstrual bleeding is well documented. A systematic review of 26 RCTs reported that across the studies investigating the use of the LNG-IUS, there was a 71–95 % reduction in menstrual bleeding in women whose uterine bleeding was abnormal as a presumed consequence of endometrial dysfunction (Matteson et al. 2013). The authors recommended the use of the LNG-IUS for the management of such bleeding, over other effective treatments such as combined oral contraceptives, non-steroidal anti-inflammatory drugs and luteal phase progestogens (Matteson et al. 2013). In the US, it has been suggested that the LNG-IUS may be the most cost effective intervention for those who wish to preserve fertility (Ganz et al. 2013).

In comparison to surgical interventions, a Cochrane review (Lethaby et al. 2005) reported that the LNG-IUS is associated with a smaller reduction in blood loss than endometrial ablation, more progestogenic side effects than transcervical resection of the endometrium (TCRE) and, based on the findings from one Finnish study, fewer costs than hysterectomy. Quality of life and satisfaction appeared to be comparable (Lethaby et al. 2005). A subsequent RCT reported that at 5 years, when compared to LNG-IUS users, those who had undergone thermal balloon ablation had significantly higher menstrual blood loss (45.5 % vs 0.0 % p < .001) and were more likely to have gone on to have a hysterectomy (Silva-Filho et al. 2013). An LNG-IUS is less invasive and associated with fewer major risks than hysterectomy, although women may be more likely to require additional interventions (Matteson et al. 2013). A cost effectiveness analysis in the UK using a Markov model suggested that the LNG-IUS is less cost effective than hysterectomy (Roberts et al. 2011). However, the authors noted that the findings may be at odds with an approach that is individualised to the woman and promotes choice (Roberts et al. 2011).

While trials comparing two lower dose LNG-IUS methods (13.5mg and 19.5mg respectively) with the 52 mg LNG-IUS have shown reduced bleeding over time with all three methods, the proportion of women benefitting from this is smaller with the lower doses of LNG (Gemzell-Danielsson et al. 2012). Women with iron deficiency anaemia, as a consequence of heavy menstrual bleeding, may benefit from use of the LNG-IUS but more studies are required (Lowe and Prata 2013).

Risks of Intrauterine Devices

Breast Cancer

As with other progestogen-only contraceptive methods, there is a paucity of evidence in relation to breast cancer and the LNG-IUS (Curtis et al. 2007). A large post-marketing surveillance study from Finland found no difference in the risk of breast cancer in users of the LNG-IUS compared to the general population in women aged 30–54 years (Backman et al. 2005). Similarly no increased risk of breast cancer was observed amongst ever users or current users of the Cu-IUD or LNG-IUS in a retrospective, population-based, case-control study powered to exclude a 1.5-fold risk of breast cancer in women under 50 years of age (Dinger et al. 2011). One case-control study which utilised registry data reported that use of the LNG-IUS was associated with an increased risk of breast cancer in newly postmenopausal Finnish women when used on its own or in conjunction with estradiol (Lyytinen et al. 2010). The authors noted that this finding was unexpected and it may be that the findings are the result of bias and confounding.

Little is known about the impact of LNG-IUS use on breast cancer recurrence. However use is generally not advised in women who have breast cancer or those with a past history of breast cancer (Centre for Disease Control and Prevention 2010; Faculty of Sexual and Reproductive Healthcare 2009a; World Health Organization 2010).

VTE and Cardiovascular Disease

Whilst limited, the available data, as with other progestogen-only methods (Chakhtoura et al. 2011), do not suggest a woman’s risk of VTE is increased by use of the LNG-IUS (Lidegaard et al. 2012a; Mantha et al. 2012). Subgroup analysis data from a meta-analysis of the eight included observational studies reported that, from the two studies that included information on the LNG-IUS, the relative risk of VTE was not statistically significant (0.61 (95 % CI 0.24–1.53)) (Mantha et al. 2012).

Bone Mineral Density

There is no known association between use of the LNG-IUS and reduced bone mineral density. Comparative studies of the LNG-IUS and Cu-IUD have not reported any significant differences between users of the two methods (Bahamondes et al. 2006b2010).

Ectopic Pregnancy

A previous history of ectopic pregnancy is a risk factor for further ectopic pregnancies: medical eligibility criteria for contraceptive use do not however suggest that a previous ectopic pregnancy is a condition that restricts use of intrauterine contraceptives (Centre for Disease Control and Prevention 2010; Faculty of Sexual and Reproductive Healthcare 2009a; World Health Organization 2010). As with the progestogen-only implant, the absolute risk of ectopic pregnancy is low because a woman’s overall risk of pregnancy is markedly reduced by the use of intrauterine contraception (Xiong et al. 1995; Skjeldestad 1997; Ory 1981; Rossing et al. 1993; World Health Organization 1985). The UK National Institute for Health and Care Excellence (NICE) (National Institute for Health and Care Excellence 2005) reports that with 5 years of use, the overall risk of ectopic pregnancy for those using intrauterine contraceptives is less than 1 in 1,000. An absolute ectopic pregnancy rate of 0.10 per 100 woman-years (95 % CI 0.02–0.29) has been reported for the 13.5 mg LNG-IUS (Nelson et al. 2013). No studies have been sufficiently powered to compare ectopic pregnancy rates between the 13.5 and 52 mg LNG devices.

However, if a woman does experience a pregnancy with an intrauterine method in situ, the proportion of ectopic pregnancies may be increased (Xiong et al. 1995). In a cross-sectional study of 17,360 users of the LNG-IUS, of the 64 pregnancies that occurred with a LNG-IUS in situ, over half (53 %) were ectopic (Backman et al. 2004). A cohort study reported around 39 % of pregnancies that occurred with an LNG-IUS in situ were ectopic compared with around 18 % of those with a Cu-IUD (Heinemann et al. 2013a). Similarly, in phase II and phase III trials of the 13.5 mg LNG-IUS, up to 50 % of the occurring pregnancies were ectopic but the numbers of women becoming pregnant in these studies was small (n = 2 and n = 7 respectively) (Nelson et al. 2013; Gemzell-Danielsson et al. 2012). It is therefore advised that ectopic pregnancy be excluded in women who become pregnant with an intrauterine contraceptive method in situ and that women themselves are informed about the possibility of ectopic pregnancy and associated symptoms for example unilateral abdominal pain and vaginal bleeding (Bayer PLC 20132014; Faculty of Sexual and Reproductive Healthcare 2015).

Expulsion

Expulsion of an intrauterine contraceptive method usually occurs in the first few months following insertion and alongside menstruation (National Institute for Health and Care Excellence 2005; World Health Organization 1987). Such events leave a woman vulnerable to an unintended pregnancy, therefore women should be informed about how to check for signs of expulsion and what to do if expulsion is suspected (National Institute for Health and Care Excellence 2005; Faculty of Sexual and Reproductive Healthcare 2015). However, it is reported that at 5 years of use, less than 5 % of women will have experienced an expulsion (National Institute for Health and Care Excellence 2005). The rate of expulsion does not appear to be influenced by the timing within the menstrual cycle that a Cu-IUD is fitted; no evidence is available for the LNG-IUS (Whiteman et al. 2013). However, when and how an intrauterine method is inserted post-partum and post-abortion does appear to exert some influence on the rate of expulsion. Expulsion rates following insertion of an IUD immediately following a vaginal delivery are higher than if the method is inserted during caesarean section (Goldstuck and Steyn 2013; Kapp and Curtis 2009). Waiting until more than 6 weeks post vaginal delivery appears to be associated with fewer expulsions than if the device is inserted in the first 48 h post-delivery (Kapp and Curtis 2009; Grimes et al. 2010a). Similar findings have been reported for post-abortion insertion (Grimes et al. 2010b).

Generally the type of framed Cu-IUD has not been found to influence the rate of expulsion (Kulier et al. 2007). The impact of modifying the frameless IUD inserter on early problems with expulsion is not known (O’Brien and Marfleet 2005). A Cochrane review of RCTs reported that the LNG-IUS has a higher rate of expulsion than Cu-IUDs containing more than 250 mm2 (French et al. 2004), although the reverse has also been documented (Aoun et al. 2014).

During 3 years of use, the cumulative risk of partial or complete expulsion associated with the 13.5 mg LNG-IUS was under 5 % (Nelson et al. 2013).

Pelvic Inflammatory Disease

There have long been concerns that use of intrauterine methods increases a woman’s risk of developing pelvic inflammatory disease (PID). As pelvic inflammatory disease is largely the result of a bacterial infection ascending from the cervix into the upper reproductive tract, the concern is predominantly that insertion of an intrauterine device may facilitate this process. The evidence supporting this concern is lacking (Farley et al. 1992; Grimes 2000) and generally much of the available evidence in this area is subject to limitations, confounding, and bias (Hubacher et al. 2013).

The insertion procedure and a woman’s background risk of sexually transmitted infections (STIs) are the most likely contributing factors to the development of PID in intrauterine device users (Farley et al. 1992). In the first 20 days following insertion, the risk of PID is increased sixfold but remains low thereafter (Farley et al. 1992). The risk of PID is lower amongst women who have an IUD inserted in the absence of chlamydia or gonorrhoea; the risk for women with an STI appears similar, regardless of whether an intrauterine contraceptive device is inserted or not (Grimes 2000). NICE reports that PID may occur in fewer than 1 in 100 in women who are at low risk of sexually transmitted infections (National Institute for Health and Care Excellence 2005). Even in young women for whom their age means they are at increased risk of sexually transmitted infections and consequently PID, the benefits of IUD use are felt to outweigh any potential or theoretical risk (Centre for Disease Control and Prevention 2010; Faculty of Sexual and Reproductive Healthcare 2009a; World Health Organization 2010; Carr and Espey 2013). However, in the presence of purulent cervicitis from chlamydia or gonorrhoea, or in symptomatic women awaiting test results, insertion of an intrauterine contraceptive device should be delayed (Centre for Disease Control and Prevention 2010; Faculty of Sexual and Reproductive Healthcare 2009a; World Health Organization 2010).

While background risk of STIs appears to be an influencing factor for developing PID, the type of Cu-IUD does not (Farley et al. 1992). There is conflicting evidence as to whether the LNG-IUS is associated with a lower risk than the Cu-IUD (Grimes 2000). A multicentre RCT which compared the copper IUD (Nova T) to the LNG-IUS (20 μg/daily) found that the cumulative rate of PID amongst women using the LNG-IUS was lower at 36 months than with the Cu-IUD (0.5 and 2.0 respectively) (Toivonen et al. 1991) whereas similar rates of PID were found in other studies comparing Cu-IUDs to hormonal IUDs (Sivin et al. 1991). In these two studies use of Cu-IUDs was not found to be associated with a higher rate of discontinuation due to PID than the LNG-IUS (Sivin et al. 1991; Toivonen et al. 1991). A systematic review concluded that incidence of PID amongst Cu-IUD users differs little to that experienced by women initiating other methods of contraception such as the LNG-IUS, the progestogen-only injectable or combined oral methods of contraception (Steenland et al. 2013).

For women who do develop PID with an intrauterine contraceptive device in situ, there appears to be no clear advantage in terms of clinical outcomes to having it removed for treatment (Tepper et al. 2013).

Perforation

Uterine perforations are a rare, yet potentially life threatening complication of intrauterine contraceptive use, which nearly always occur at the time of insertion but can often be asymptomatic (National Institute for Health and Care Excellence 2005; Kaislasuo et al. 2012; Harrison-Woolrych et al. 2003; Caliskan et al. 2003) and are sometimes not identified until months or years after insertion (Harrison-Woolrych et al. 2003; van Grootheest et al. 2011; Kaislasuo et al. 2013). An intrauterine device is not thought to ‘migrate’ through the uterine wall. However, less commonly an intrauterine device may penetrate into the myometrium: this is termed partial perforation (Zakin et al. 1981).

Perforation rates of less than 1 in every 1,000 intrauterine contraceptive device insertions are quoted (National Institute for Health and Care Excellence 2005), although rates observed in controlled clinical trials may be lower than those from real life situations and higher incidences have been documented, including in large cohort studies (Harrison-Woolrych et al. 2003; Caliskan et al. 2003). In the UK MHRA spontaneous reporting database, under levonorgestrel single agent products, there are 105 uterine perforations listed. Whilst the LNG-IUS is one of a number of single agent products listed, it would seem most likely that these reports relate to this product.

Rates of perforation with any IUD may in part be influenced by the maintenance of the skill of the operator. In a large prospective observational cohort study of a copper IUD, doctors who had inserted fewer than 10 IUDs during the 10 year study period, (73 % of the sample) had significantly higher reported perforation rates than those who had inserted between 10 and 99 (Harrison-Woolrych et al. 2003).

Perforation typically occurs into the utero-rectal pouch with an anteverted uterus or vesicouterine pouch if retroverted (Zakin et al. 1981). It can also occur through the fundus particularly if the uterus is in an axial position. Usually the device, once translocated into the abdominal cavity, is free. Devices in the abdominal cavity may become adherent to omentum. There are very rare reports of perforation beyond the uterus into the bowel (Sarkar 2000; Rowlands 2010b).

The effect of breastfeeding or insertion during the postpartum period on perforation rates has been debated for over 25 years. A systematic review of poor to fair quality trials suggested that there is no increased risk of complications such as perforation when intrauterine methods are inserted in the postpartum period (Kapp and Curtis 2009). A number of studies suggest that uterine perforations with an intrauterine contraceptive method appear to be more common when a woman is breastfeeding (Kaislasuo et al. 2012; Harrison-Woolrych et al. 2003; Andersson et al. 1998; Heinemann et al. 2013b2014). However, that said, Medical Eligibility Criteria (Centre for Disease Control and Prevention 2010; Faculty of Sexual and Reproductive Healthcare 2009a; World Health Organization 2010) do not currently warn that the risk of perforation is increased by insertion in the postpartum period or amongst breastfeeding women. The type of Cu-IUD does not appear to be an influencing factor in perforation rates (O’Brien and Marfleet 2005).

The crude incidence for complete or partial perforation has been very low (0–0.03 %) in clinical trials of low dose levonorgestrel intrauterine devices (Nelson et al. 2013; Gemzell-Danielsson et al. 2012).

Sepsis

Whilst a very rare occurrence, cases of invasive group A streptococcus have been reported following insertion of intrauterine contraceptive methods (Venkataramanasetty et al. 2009; Saleh et al. 2011; Gisser et al. 2002; Cho and Fernando 2013). Although asymptomatic women do not need to be screened for group A streptococcus prior to IUD insertion, women found to be carrying the organism in the vagina should be treated (Faculty of Sexual and Reproductive Healthcare 2015).

Vasovagal Syncope

Vasovagal syncope can occur after cervical dilatation and instrumentation of the uterus. Such events usually resolve quickly and rarely do such events require more than basic resuscitation measures. However, where bradycardia persists, further interventions may be required. The risk of this adverse event associated with IUD insertion is a reason for clinics to have resuscitation facilities on hand.

Removal Difficulties

Intrauterine devices are sometimes difficult to remove. There are various reasons for this. Some IUDs become embedded in the myometrium; such cases need careful assessment (Zakin et al. 1981). Postmenopausal women may need estrogen treatment to counteract atrophic changes before removal is possible. Intrauterine devices should not be left in situ in postmenopausal women because of the risk of pyometra.

Occasionally the threads break off from the vertical stem of the device. There are also some threadless devices. There are millions of women who have had stainless steel ring IUDs inserted in China. When these need removal a hook or alligator forceps will be needed (Cheung 2010; Penney et al. 2006).

Side Effects of Intrauterine Devices

Both Cu-IUDs and the LNG-IUS are associated with adverse effects and these will be described in this section. Despite containing a lower dose of progestogen than the LNG-IUS, the 13.5mg LNG-IUS has a similar side effect profile to that of the LNG-IUS (Gemzell-Danielsson et al. 2012). Where evidence to the contrary is available this will be specified.

Acne, Breast Tenderness, Headache, Libido and Mood Changes

As with other hormonal methods, product information for the LNG-IUS lists a number of systemic side effects commonly (≥1/100 to <1/10) noted in clinical trials, including acne, breast tenderness, headache, libido and mood change. Hormonal side effects may result in higher removal rates than with use of Cu-IUDs (Chi 1991). There is relatively little comparative data from which to draw conclusions, however at 5 years when compared to non-hormonal IUDs, their side effect profiles have not been found to differ significantly (French et al. 2000). Use of intrauterine methods of contraception does not appear to negatively affect libido (Enzlin et al. 2012; Martin-Loeches et al. 2003; Bastianelli et al. 2011; Li et al. 2004).

Altered Bleeding Patterns

Initially, following insertion of an intrauterine device, bleeding patterns are often irregular, frequent or prolonged (Suvisaari and Lahteenmaki 1996). These patterns appear to improve with time (Suvisaari and Lahteenmaki 1996; Datey et al. 1995). However, for some women irregular bleeding will continue (Suvisaari and Lahteenmaki 1996; Hubacher et al. 2009), with one study reporting that irregular bleeding was still present in around 20 % of women at 12 months of use (Suvisaari and Lahteenmaki 1996).

After using the LNG-IUS for 12 months or more, women are more likely to move towards infrequent bleeding or amenorrhoea (Suvisaari and Lahteenmaki 1996). This is not the case with use of Cu-IUDs. With the lower dose 13.5mg LNG-IUS the proportion of women experiencing amenorrhoea may be less than with the 52 mg LNG-IUS (Gemzell-Danielsson et al. 2012).

For both Cu-IUDs and the LNG-IUS, altered menstrual bleeding patterns are a reason often given for method discontinuation (National Institute for Health and Care Excellence 2005; Cox et al. 2002; Wong et al. 2009). A study designed to investigate characteristics associated with discontinuation and reasons for discontinuation of LARC methods reported that at 6 months, of those who discontinued their LNG-IUS before 6 months, 10 % (n = 14) reported doing so because of irregular or prolonged bleeding. The corresponding figure for those who had discontinued their Cu-IUD was 19.2 % (n = 10). Interestingly, amenorrhoea is a common reason for discontinuation of the LNG-IUS; some women appear to seek regular reassurance that they are not pregnant.

In terms of managing such bleeding, non-steroidal anti-inflammatory drugs (NSAIDs), may offer some benefit to women using Cu-IUDs (Godfrey et al. 2013). Long-term strategies to manage problematic bleeding associated with the LNG-IUS are lacking (Abdel-Aleem et al. 2013a). Guidance in the UK suggests trying a combined oral contraceptive for women experiencing unscheduled bleeding with the LNG-IUS (Faculty of Sexual and Reproductive Healthcare 2009b).

Ovarian Cysts

Ovarian cysts are documented in the Summary of Product Characteristics for the LNG-IUS (Bayer PLC 2013) and 13.5 mg LNG-IUS (Bayer PLC 2014) as commonly (>1/100 to <1/10) /very commonly (>1/10) reported in clinical trials. In a comparative trial, compared with the LNG-IUS, significantly fewer ovarian cysts were observed in women using lower dose levonorgestrel intrauterine systems (Gemzell-Danielsson et al. 2012).

Such cysts are not thought to present a clinical problem as they often resolve of their own accord. In a study of women with heavy menstrual bleeding, a higher incidence of ovarian cysts was found in those using an LNG-IUS compared to those who had undergone a hysterectomy (17.5 % vs 3 %) (21.5 % vs 8 %) at 6 and 12 months respectively (Inki et al. 2002): the cysts observed in women using the LNG-IUS tended to be small, asymptomatic, and 94 % resolved spontaneously. In a 5 year RCT comparing the LNG-IUS to a Cu-IUD, a non-significant increased risk of ovarian cyst formation was observed with use of the LNG-IUS: 1.5 (95 % CI, 0.51–4.4). Discontinuation rates for enlarged follicles were similar for the LNG-IUS and Cu-IUD: 0.09 and 0.07 per 100 women respectively (Andersson et al. 1994).

Weight Gain

Weight gain has been noted as a side effect in trials of Cu-IUDs and the LNG-IUS (Andersson et al. 1994; Sheng et al. 2009). However as a non-hormonal device, no effect on weight would be expected with the Cu-IUD and any observed gain is unlikely to be the result of this method of contraception. In trials comparing the LNG-IUS to the Cu-IUD no significant differences in documented (Dal’Ava et al. 2012) or perceived weight change (Nault et al. 2013) has been shown. Body composition has similarly not been found to be significantly different following 12 months of use, although LNG-IUS users demonstrated a significant increase in fat mass and loss of lean mass, whilst Cu-IUD users demonstrated a non-significant loss of fat mass and gain of lean mass (Dal’Ava et al. 2012). There is little evidence to suggest that use of progestogen-only contraceptives is associated with weight gain (Lopez et al. 2013a).

Return of Fertility After Use of Intrauterine Devices

Concerns about the effect on fertility has been cited as a reason for wariness in relation to long-acting contraceptives (Glasier et al. 2008). A cohort study (Doll et al. 2001) of nulliparous married women in Scotland and England reported that, even when controlling for potential confounding such as age and gynaecological history, there appeared to be an association between increased duration of IUD use and decreased fertility. Women who had used their device for 78 months or more had less favourable fertility patterns at 12 months after stopping than those who had used it for less than 42 months (28 % had delivered compared with 46 %) (Doll et al. 2001).

However, findings from other studies would generally suggest that women can largely be reassured that there does not appear to be a delay in return to fertility following use of intrauterine methods (Wilson 1989; Mansour et al. 2011) or an increase in the risk of tubal occlusion and infertility (Vessey et al. 1983; Hov et al. 2007). A non-systematic review of the literature has suggested that 1 year after stopping use of intrauterine methods, similar rates of pregnancies would be expected for these women as for those who had used no contraception or who had stopped using condoms (Mansour et al. 2011). Guidance indicates that women can be informed that after stopping their method that there is no delay (National Institute for Health and Care Excellence 2005; Faculty of Sexual and Reproductive Healthcare 2015).

Use of Intrauterine Devices by Young and/or Nulliparous Women

Provision of intrauterine methods to young or nulliparous women is often resisted due to misconceptions amongst healthcare providers as to the safety of these methods (Tyler et al. 2012). Although there is some evidence to suggest expulsion rates may be higher in young women (Deans and Grimes 2009), there is no reason to deny a young person an intrauterine method on the basis of age or parity alone; in fact, medical eligibility criteria indicate that parity (parous or nulliparous) does not place any restriction on the use of intrauterine methods (Centre for Disease Control and Prevention 2010; Faculty of Sexual and Reproductive Healthcare 2009a; World Health Organization 2010). Although nulliparity is not listed as a contraindication to use, the licence for the 13.5 mg LNG-IUS suggests that it should not be first choice for nulliparous women (Bayer PLC 2014).

Section Summary: Intrauterine Devices

Intrauterine methods of contraception confer similar protection against pregnancy as sterilisation and are therefore highly effective. The LNG-IUS is licensed for use as a contraceptive for up to 5 years; the 13.5mg LNG-IUS can be used for up to 3 years. Depending on the device, Cu-IUDs can be used for between 5 and 10 years. In some circumstances intrauterine devices may be used for longer, for example when women are over the age of 45 years at the time they have their LNG-IUS inserted. Such use however, would be outside the terms of the product licence.

Studies to date have not demonstrated an association between use of intrauterine methods and cancer, indeed they may offer women some protection against endometrial cancer. Concerns about pelvic inflammatory disease and infertility appear to be largely unfounded; the risk is mediated in part by a woman’s background risk of sexually transmitted infections, and after the first few weeks following insertion, a woman’s risk is generally no higher than it would have been before insertion. Uterine perforations can occur during IUD insertion, but rarely do. There does not appear to be any way to ameliorate this risk, therefore women should be advised about thread checking and signs/symptoms that may be indicative of uterine perforation.

An ectopic pregnancy is a potentially life threatening event. Women who use intrauterine contraceptives are largely protected from ectopic pregnancy by the very fact they are using such an effective method of contraception. However, health professionals should be aware, that if these methods fail, the chance of the pregnancy being ectopic is higher than for women not using contraception. There is no reason why nulliparous women cannot safely use intrauterine contraceptive methods if they choose to, although the licence for the 13.5 mg LNG-IUS advises it should not be first choice for nulliparous women.

Combined Hormonal Patch and Vaginal Ring

In addition to combined oral contraceptives (COCs), which were discussed in Chap. 5, a combined vaginal ring (Nuvaring®) and a combined transdermal patch (Evra®, Evra 3®, Ortho Evra®) are available to women in many countries for example the United States, Canada, Australia, and throughout Europe. Whereas the combined vaginal ring is available in New Zealand, the transdermal patch is not.

The combined vaginal ring contains 2.7 mg of ethinylestradiol and 11.7 mg etonogestrel which are released at a rate of 0.015 and 0.120 mg per 24 h respectively (Merck Sharpe and Dohme 2014).

The active hormones within the transdermal patch are ethinylestradiol and norelgestromin. The total content and release rates vary slightly depending on whether it is OrthoEvra or Evra but both currently marketed products release approximately 35 μg of ethinylestradiol a day (Janssen-Cilag 2014; Janssen Pharmaceuticals 2014). The daily release rate of norelgestromin from OrthoEvra is quoted as 150 μg (Janssen Pharmaceuticals 2014); in the UK for Evra it is quoted as 203 μg (Janssen-Cilag 2014).

In the UK, the licensed advice, according to the Summary of Product Characteristics, is that the contraceptive ring is inserted into the vagina and worn for 3 weeks (Merck Sharpe and Dohme Limited 2014). It is then removed for 1 week following which a new ring is inserted. The contraceptive patch requires a new patch to be applied and replaced weekly for 3 weeks, followed by a 7-day hormone free interval (Janssen-Cilag 2014). Extended regimens e.g. omitting the ring-or patch-free interval can be used but would be outside the terms of the product licence (Faculty of Sexual and Reproductive Healthcare 2011b).

Effectiveness of the Vaginal Ring and Patch

The effectiveness of the combined vaginal ring and patch have each been shown to be comparable with that of COCs (Lopez et al. 2013b). Oral methods undergo extensive first pass metabolism and therefore their efficacy is affected by factors that affect absorption such as vomiting or severe diarrhoea, whereas the ring and patch are not. However, as with oral methods, the effectiveness of the patch and ring has the potential to be affected by drugs that induce microsomal/hepatic enzymes such as certain antiepileptic, human immunodeficiency virus (HIV) and herbal medications/products (Merck Sharpe and Dohme Limited 2014; Janssen-Cilag 2014).

Eligibility Criteria for the Patch and Ring

The majority of the available epidemiological evidence for combined hormonal contraceptives relates to oral contraceptives. There is less available data for the ring and the patch. However, the WHO, US and UK Medical Eligibility Criteria for Contraceptive Use (MEC) (Centre for Disease Control and Prevention 2010; Faculty of Sexual and Reproductive Healthcare 2009a; World Health Organization 2010) generally apply the same restrictions to these methods as to COCs and therefore the same cautions and considerations should broadly be applied to these methods as to COCs. Likewise, although direct evidence is scant, if the risks are assumed to be similar, it would be reasonable to assume that the beneficial effects may also extend to these methods.

Safety Profile

As with COCs, cycle control with these two combined hormonal methods is good (Lopez et al. 2013b). The side effect profiles are generally similar to those experienced with the COC (Lopez et al. 2013b), although there are some notable differences. A Cochrane review noted that compared with COC use, those who used the ethinylestradiol/etonogestrel vaginal ring were less likely to experience nausea, acne, irritability, depression and mood changes and were less likely to discontinue their method due to adverse events than COC users (Lopez et al. 2013b). Ring users were however more likely to report vaginal irritation and discharge than COC users (Lopez et al. 2013b), which could in theory be in part a consequence of their route of administration.

However, norelgestromin/ethinylestradiol patch users were more likely to experience breast discomfort, dysmenorrhea, nausea, and vomiting and compared to COC users were significantly more likely to discontinue due to adverse events (Lopez et al. 2013b).

In 2006 the application for the EVRA (norelgestromin/estradiol) patch was declined in NZ because of an unfavourable risk: benefit assessment, with concerns noted about the high incidence of estrogenic side effects (Medsafe. Extract from 78th MAAC minutes. 2006). In the US, product information for OrthoEvraÛ states that the estrogen exposure is 60 % higher than if taking an oral contraceptive containing 35 μg of ethinylestradiol (Janssen Pharmaceuticals 2014).

Risk of Venous Thromboembolism

As with COCs, one of the biggest safety concerns, in relation to the use of these combined hormonal devices is the risk of thrombosis (see Chap. 6). The ring and patch contain ‘newer’ generation progestogens and, as discussed in Chaps. 5 and 6, there has been much interest in the impact these progestogens have on mediating thrombosis and cardiovascular risk. While some studies have suggested that, in comparison to COCs containing ‘older’ progestogens such as levonorgestrel and norethisterone, the transdermal patch presents a generally similar level of venous thromboembolism (VTE) risk (Jick et al. 200620072010), others have suggested that the risk is greater (Lidegaard et al. 2012a; Cole et al. 2007; Dore et al. 2010; European Medicines Agency 2014).

While there is less available data for the combined vaginal ring, reported findings regarding risk of VTE are also conflicting (Lidegaard et al. 2012a; Sidney et al. 2013). No studies to date have suggested a decreased risk for either the patch or the ring compared with oral contraceptive pills and therefore despite the ring being lower dose, there is no apparent benefit in terms of VTE risk in the use of a non-oral method.

The European Medicines Agency (European Medicines Agency 2014) published findings of a review in 2013 which stated that certain progestogens (including those in the patch and ring) are associated with an increased risk of thrombosis compared to others. However, the absolute risk of VTE they report is generally very low with combined hormonal contraceptive methods containing less than 50 μg of ethinylestradiol (5–12 per 10,000 women depending on the progestogen used- see Chaps. 6 and 14) and the conclusion is that for most women the benefits of combined hormonal contraceptives outweigh the risks when prescribed appropriately (European Medicines Agency 2014).

Vaginal Ring for Lactating Women

A progesterone releasing ring is available for breastfeeding women in Latin America. It is inserted once every 3 months for as long as breastfeeding continues, helping to prolong amenorrhoea and reduce the number of bleeding/spotting episodes (Nath and Sitruk-Ware 2010). Amongst breastfeeding women it has been shown, at 1 year, to compare favourably with the IUD use in terms of efficacy (Sivin et al. 1997). Over the 3 month period, the flexible silicone ring releases progesterone at an average rate of 10 mg/day (Nath and Sitruk-Ware 2010). No adverse effect on breastfeeding outcomes or infant growth has been shown with the use of this method (Nath and Sitruk-Ware 2010). Vaginal complaints may be more common with use of the progesterone releasing ring as compared with the IUD (Nath and Sitruk-Ware 2010; Sivin et al. 1997).

Section Summary: Combined Hormonal Patch and Vaginal Ring

There are a number of currently marketed hormonal contraceptive devices and many more under development. Long-term data from epidemiological studies on combined contraceptive devices such as the transdermal patch and vaginal ring are lacking. However, studies which have looked at VTE risk do not suggest any potential benefit to non-oral routes. The risks associated with use of these combined contraceptive devices are taken to be the same as for combined oral contraceptives with similar prescribing restrictions applied.

The transdermal patch and vaginal ring have been approved for use in several major markets including the UK and the USA, which indicates that the benefit to risk assessment was considered favourable for the licensed indications. In other words, the benefits of contraceptive protection provided by these devices outweighed the risks of adverse events. However it should be noted that the evidence to support approval is derived mainly from clinical trials and longer term studies of post-marketing use are required. It should also be noted that the combined contraceptive patch EVRA® has not been approved in all markets.

Take Home Messages

·               Progestogen-only implants and intrauterine contraceptive devices are highly effective methods of contraception.

·               Progestogen-only implants and intrauterine devices are generally very safe.

·               Many of the risks associated with use of the progestogen-only implant are a consequence of the insertion and removal procedure, not the device itself; therefore there is scope for reducing these risks.

·               The most commonly experienced side effect of progestogen-only devices is irregular vaginal bleeding

·               Perforation of the uterus is a recognised but rare complication of intrauterine device insertion; there is no obvious way of significantly reducing the incidence.

·               Use of intrauterine contraceptive devices does not need to be restricted to parous or older women.

·               Further research is needed with regard to efficacy in women of heavier weight and the safety of progestogen-only methods in high risk populations.

·               Initially, following insertion of intrauterine methods of contraception women may experience changes to their regular bleeding patterns- with time, absent or infrequent bleeding is likely with the use of the LNG-IUS.

·               In many countries, newer hormonal contraceptive devices are now available, including a transdermal patch and a vaginal ring

·               Although in some countries the transdermal patch has not been licensed, currently available medical eligibility criteria consider that contraceptive devices releasing estrogen and progestogen directly through skin or mucous membrane are considered to have similar risk and benefit profiles as combined oral contraceptives.

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