7.1 Contraceptive effectiveness during extended use of the etonogestrel implant

Key information

• C.  The limited available evidence indicates that the risk of pregnancy during the fourth year of use of an ENG-IMP is likely to be very low.

Clinical recommendations

• ✓  HCPs can advise individuals who present after unprotected intercourse during the fourth year of use of an ENG-IMP that pregnancy risk is likely to be very low and EC is unlikely to be required.

• ✓  Routine use of the ENG-IMP for longer than 3 years is not currently recommended. This is because available evidence is too limited to enable users to be given accurate information about effectiveness during extended use.

In some centres outside the UK, use of each ENG-IMP for contraception is routinely extended beyond the licensed 3 years. The limited available evidence suggests that risk of pregnancy in the fourth year of use of a single ENG-IMP is likely to be very low. The evidence is, however, too limited to inform whether contraceptive effectiveness during the fourth year of use of an ENG-IMP is as high as that during the first 3 years.

A 2019 systematic review41 identified five observational studies of extended use. These studies recorded no pregnancies amongst a total of 783 women who chose to extend use of the ENG-IMP to 4 years and 306 women who continued use for 5 years. These study populations were small and may not be representative of the general population; use of additional contraception was not recorded. See also evidence relating to serum ENG levels during extended use (Section 6).

The GDG recommends that an individual who presents after UPSI during the fourth year of use of the ENG-IMP can be advised that risk of pregnancy is likely to be very low and EC is unlikely to be required. So long as a pregnancy test is negative, an individual in this situation can quick start a suitable method of contraception (see Table 6 and Table 7), with advice to use condoms until the new method becomes effective; they should have a follow-up pregnancy test 21 days after the last UPSI.

The GDG considers, however, that routine use of the ENG-IMP beyond the licensed 3 years cannot be recommended. This is because ENG-IMP users expect very high contraceptive effectiveness, and the available evidence is currently too limited to enable users to be given accurate information about contraceptive effectiveness during extended use. The contraceptive effectiveness of an ENG-IMP in its fourth year of use is, however, likely to compare favourably with typical use of user-dependent contraceptive methods.

7.2 What drug interactions are important to consider?

7.3 What is the effect of weight/body mass index on contraceptive effectiveness?

Key information

• C.  The available evidence suggests that contraceptive effectiveness of the ENG-IMP is not affected by body weight or BMI.

No studies have been specifically designed to assess how obesity impacts effectiveness of the ENG-IMP. Currently available pharmacokinetic and clinical data suggest that (for the 3-year licensed duration of use) the ENG-IMP is highly effective for contraception in individuals with raised BMI. However, data for those with BMI ≥40 kg/m²are still lacking. It is noted that in a cohort study that reported no pregnancies amongst 223 women who extended ENG-IMP use to 4 years and 102 women who extended use to 5 years, about half of the subjects had a BMI >30 kg/m2.6 Early replacement of the ENG-IMP on the basis of higher weight or BMI is not recommended (see FSRH Clinical Guideline Overweight, Obesity and Contraception47).

7.4 Contraceptive effectiveness of bent or broken implants

Refer to Section 20.

7.5 Pregnancy diagnosed when there is an etonogestrel implant in situ

Contraceptive failure is rare during use of the ENG-IMP, thus published evidence regarding outcomes in pregnancies exposed to ENG-IMP is limited to a few case reports.48 There is, however, no evidence that suggests a teratogenic effect (see FSRH Clinical Guideline Quick Starting Contraception48 Section 4.1.3: Fetal exposure to progestogen-only implant: pregnancy outcomes and risk of fetal abnormality).

If pregnancy is diagnosed in an individual with an ENG-IMP in situ and they opt to continue with the pregnancy, it is established practice that the implant should be removed. If they opt for abortion, the GDG recommends that the ENG-IMP can remain in situ during medical or surgical abortion to provide contraception afterwards; this guidance extrapolates from evidence indicating that success of medical abortion is not affected by ENG-IMP initiation at the time of mifepristone administration49 (see FSRH Clinical Guideline Contraception After Pregnancy49). If the pregnancy was conceived during established use of the ENG-IMP (rather than prior to the ENG-IMP becoming effective), HCPs should check for drug interactions. If true contraceptive failure of the ENG-IMP is suspected, the user may wish to consider an alternative contraceptive method.

8.1 Medical eligibility

8.2 Assessment of factors that could affect contraceptive effectiveness

A drug history should identify any prescribed or non-prescribed drug that could affect the contraceptive effectiveness of the ENG-IMP or could itself be affected by ENG (see Section 7.2).

9.1 Dysmenorrhoea

Key information

• C.  Most individuals with dysmenorrhoea at baseline report improvement in dysmenorrhoea with use of the ENG-IMP. A few individuals report new onset or worsening of dysmenorrhoea with ENG-IMP use.

The evidence

Some of the original manufacturer-sponsored clinical cohort trials18,53 of the ENG-IMP collected data for rates and severity of dysmenorrhoea at baseline and at end of treatment. Combined analysis of dysmenorrhoea data for 647 women in five of these studies was presented by Mansour et al in 2008. Amongst the 49% of study participants who reported mild, moderate or severe dysmenorrhoea at baseline, 77% had complete resolution and 6% decreased severity at end of treatment. Some 5.5% of all participants reported new onset or worsening of dysmenorrhoea.54 In a more recent manufacturer-sponsored cohort study of 301 women, 3.7% of women reported dysmenorrhoea during use of the ENG-IMP that was considered to be related to or possibly related to the implant.2

Smaller studies indicate similar reduction in dysmenorrhoea associated with use of the ENG-IMP. A cohort study of 41 women in Turkey55 reported dysmenorrhoea in 41.5% at baseline and only 2.4% after 6 months of use of the ENG-IMP. In Egypt, 23 women with pelvic pain considered to be due to pelvic congestion syndrome were randomised to use of the ENG-IMP (n=12) or no treatment (n=11).56 Mean visual analogue scores for dysmenorrhoea fell significantly in the ENG-IMP group, but not in the control group over the 12-month study period. In a small prospective cohort study57 of use of the ENG-IMP by 17 women with adenomyosis-associated dysmenorrhoea, all participants reported reduced dysmenorrhoea by 3 months after insertion; mean visual analogue pain score was statistically significantly lower at 3 months than at baseline, with the improvement maintained at 12 months. Almost a third of the participants were amenorrhoeic at 12 months and a quarter reported infrequent bleeding.

9.2 Heavy menstrual bleeding

Key information

• D.  Available evidence is too limited to allow conclusions to be drawn regarding the effect of use of the ENG-IMP on HMB.

There is little published evidence relating to effect of use of the ENG-IMP on pre-existing HMB.

The evidence

Amongst a cohort of 116 European women in a manufacturer-funded study, 48% reported “much less” or “less” bleeding intensity during ENG-IMP use compared to baseline.58 In a second cohort study in Australia59, 16% of 149 subjects reported HMB at baseline but fewer than 10% reported HMB during ENG-IMP use.

9.3 Endometriosis

Key information

• D.  The very limited available evidence suggests that use of the ENG-IMP could be associated with improvement in endometriosis-associated pain, but the evidence is limited to the first year after ENG-IMP insertion.

Very limited evidence from small, short studies suggests that use of the ENG-IMP is associated with improvement in endometriosis-related pain in the first year of use. None of the identified studies compared ENG-IMP to no treatment or considered longer-term effectiveness for this indication.

The evidence

A small Austrian study60 randomised women with symptomatic endometriosis to either ENG-IMP (n=21) or DMPA (n=20). Six months after implant insertion, visual analogue pain scores had reduced by a mean of 68% (95% CI 53%–83%) from baseline and requirement for analgesia had fallen. Lower pain scores were maintained at 12 months. There was a slightly smaller reduction in pain scores in the DMPA group. Similarly, a study in Brazil that randomised 103 women with endometriosis-associated pelvic pain, dysmenorrhoea or both to use of an ENG-IMP or a 52 mg LNG-IUS reported significantly reduced visual analogue scores in both groups for pelvic pain and dysmenorrhoea over 6 months of use.61

Two small, observational studies62,63 also observed reduction in endometriosis pain with use of the ENG-IMP. Sansone et al (2018)62 reported significant reduction in dysmenorrhoea and dyspareunia over 6 months of ENG-IMP use (maintained at 12 months) amongst 25 Italian women with endometriosis. In a short study63 of 50 Thai women with symptomatic endometriosis, significant improvement in mean pain score was reported from baseline to 3 months of use of the ENG-IMP.

9.4 Endometrial protection in polycystic ovary syndrome

Clinical recommendation

• ✓  Induction of withdrawal bleeding is not required in ENG-IMP users with polycystic ovary syndrome who are amenorrhoeic during the licensed duration of use of the ENG-IMP.

The FSRH Clinical Effectiveness Unit (CEU) is regularly asked about induction of withdrawal bleeding in women with polycystic ovary syndrome (PCOS) who are amenorrhoeic during use of progestogen-only contraception. Studies have not specifically assessed the effect of the ENG-IMP on the endometrium in individuals with PCOS; but in the general population, use of the ENG-IMP is associated with reduced endometrial thickness (see Section 14.4).

The GDG recommends that in line with established practice, induction of withdrawal bleeding is not required in individuals with PCOS who are amenorrhoeic during the first 3 years of use of an ENG-IMP.

10.1 Venous and arterial thromboembolism

Key information

• C.  The very limited available evidence suggests no significant increase in risk of venous or arterial thromboembolic events associated with current use of the ENG-IMP.

Venous thromboembolism

Evidence relating to risk of venous thromboembolism (VTE) during ENG-IMP use is extremely limited, but suggests no significant increased risk in the general population of implant users.64

The evidence

A Danish database study identified five confirmed first VTE events during 29 497 woman-years of exposure to the ENG-IMP. After adjustment for age, this represented a non-significant increased risk of confirmed VTE (relative risk (RR) 1.4; 95% CI 0.6–3.4) during use of the ENG-IMP compared with non-pregnant women using non-hormonal contraception.65 A Swedish case-control study suggested no difference between users of the ENG-IMP and non-users of hormonal contraception in the general population, but the number of implant users in the study was very small.66

Risk of VTE associated with use of the ENG-IMP by women who have already had a venous thromboembolic event is unknown.

Arterial thromboembolism

Evidence relating to risk of arterial thromboembolism (ATE) during use of the ENG-IMP is extremely limited, but suggests no significant increased risk in the general population of implant users.64

The evidence

A Danish database study67 identified three incidents of thrombotic stroke and three of myocardial infarction during 24 954 woman years of use of the ENG-IMP. The study reported no significant increased risk of either outcome in ENG-IMP users (for ENG-IMP use relative to non-use of hormonal contraception the relative risk for thrombotic stroke was 0.88 (95% CI 0.28–2.72) and for myocardial infarction relative risk was 2.14 (95% CI 0.69–6.65).

Risk of ATE associated with use of the ENG-IMP by women who have already had an arterial thromboembolic event is unknown.

10.2 Osteoporosis

Key information

• C.  The available evidence is too limited to confirm or exclude an association between ENG-IMP use and reduction in BMD.

The evidence

The Summary of Product Characteristics (SPC) for Nexplanon suggests no significant effect of ENG-IMP use on BMD.5 The SPC states that mean serum estradiol levels remain above those seen in the early follicular phase4 and references one small prospective cohort study comparing BMD in 44 ENG-IMP users and 29 Cu-IUD users before and after 2 years of use.68

In a Brazilian cohort study69 of 56 women using various methods of contraception at baseline, there was a small but significant loss of BMD at midshaft of ulna over 18 months of use of the ENG-IMP. There was, however, no significant change in BMD at distal radius. The study did not include a comparator group of women using no hormonal contraception. A later small Brazilian study70 measured BMD at femoral neck and lumbar spine at baseline and after 12 months in 23 new users of the ENG-IMP and 25 similar new users of the Cu-IUD. At 12 months, the study reported a reduction in BMD at both sites in implant users, but this was not statistically significantly different from the change in BMD for Cu-IUD users. A cross-sectional study71 reported significantly lower BMD at distal radius and ulna (but not at lumbar spine or femur) amongst 100 Thai women who had used the ENG-IMP for at least 2 years compared to 50 similar controls. None of these studies considered long-term ENG-IMP use or the clinical significance of the findings in terms of fracture risk.

The GDG interprets the existing evidence more cautiously than it has done in previous FSRH guidance and considers that there is currently inadequate evidence to confirm or exclude an association between use of the ENG-IMP and reduction in BMD. There is, however, insufficient evidence of harm to warrant routine monitoring of BMD.

10.3 Breast cancer

Key information

• D.  The available evidence suggests a possible association between current or recent use of hormonal contraception (including progestogen-only implants) and a small increase in risk of breast cancer; absolute risk remains very small.

The evidence

A large database study72 used information drawn from Danish national databases for the 1.8 million Danish women aged 15–49 years between 1995 and 2012 to assess the risk of breast cancer associated with use of hormonal contraception. Current and recent users of hormonal contraception (all methods combined) were at 20% increased risk of developing breast cancer compared to never-users of hormonal contraceptives (adjusted RR 1.20; 95% CI 1.14–1.26). Current or recent use of any progestogen-only implant (data for ENG and LNG implants are not separated) was not found to be associated with increased risk of breast cancer. When interpreting this evidence it should be noted that the number of person-years of exposure to implants in this study was small compared to, for example, combined hormonal contraception (CHC), and there were few incident breast cancers in this group. Evidence from earlier case-control studies relates to LNG rather than to ENG implants.73,74

10.4 Gynaecological cancers

Key information

• D.  The available evidence is too limited to inform whether there is any association between use of the ENG-IMP and risk of ovarian, endometrial or cervical cancer.

The evidence

A Danish database study75 suggested lower risk of ovarian cancer associated with current or recent use of any progestogen-only contraception than with never-use of hormonal contraception (adjusted RR 0.72; 95% CI 0.55–0.95). The study did not inform risk of ovarian cancer associated specifically with use of the ENG-IMP.

A small UK study published in 1998 randomised 60 women to use of an ENG or a LNG implant. Amongst the 26 ENG-IMP users that completed 24 months of ENG-IMP use, mean endometrial thickness reduced from 11.3 mm at baseline to 3.3 mm at month 12 and 3.2 mm at month 24. There was no change in cervical cytology (all samples were normal at baseline).11 Similar findings were reported by a small Scandinavian study, although of the 16 women who commenced ENG-IMP use only nine completed 2 years and seven completed 3 years of use.8

10.5 Ectopic pregnancy

Key information

• C.  The absolute risk of ectopic pregnancy during use of the ENG-IMP is extremely small.

The risk of any pregnancy (intrauterine or ectopic) during use of the ENG-IMP is extremely small (see Section 7). Note that previous ectopic pregnancy does not contraindicate use of the ENG-IMP.51

The evidence

A few individual cases of ectopic pregnancy during ENG-IMP use are reported in the literature.30–32,34,37,39,40,76 A review of clinical trials and marketing data for the ENG-IMP reported a rate of 0.2 ectopic pregnancies per 100 000 implants sold. In this study, ectopic pregnancies represented 4.7% of all reported pregnancies associated with ENG-IMP use (not all of these were confirmed on-treatment pregnancies).12 A review of postmarketing surveillance data submitted to Australia’s drug regulatory agency reported five ectopic pregnancies in 218 unintended pregnancies associated with ENG-IMP use (2.3%).30 For reference, in the UK about 1% of all pregnancies are ectopic.77

11.1 Unpredictable bleeding patterns

Key information

• ✓  Mechanisms underlying irregular bleeding with progestogen-only contraception are incompletely understood.

• C.  Irregular, unpredictable bleeding is common during use of the ENG-IMP.

• C.  Bleeding pattern may change at any time during use of an ENG-IMP.

• C.  The median number of days of bleeding/spotting during use of the ENG-IMP is lower than or comparable to that during natural menstrual cycles or standard use of combined contraception, but the pattern is less predictable.

• C.  Individuals with ‘unfavourable’ bleeding patterns in the first few months after ­ENG-IMP insertion may have about a 50% chance that bleeding will improve over time.

Clinical recommendations

• ✓  Individuals considering use of the ENG-IMP should be:

  • ▸  Advised that a change in bleeding pattern is likely;

  • ▸  Advised that bleeding pattern is unpredictable, often irregular and may change during use; and

  • ▸  Made aware how to access support for management of problematic bleeding.

• ✓  After exclusion of other causes of bleeding, ENG-IMP users with problematic bleeding who are medically eligible can be offered a 3-month trial of additional use of COC (outside the product licence) or a 5-day course of mefenamic acid.

11.2 Headache

Key information

• C.  Headache is commonly reported during ENG-IMP use; evidence is, however, too limited to confirm or exclude any causative association.

Reported incidence of headache as a side effect of ENG-IMP varies between studies. It is noted that headache reported during ENG-IMP use is not necessarily caused by the implant. The available evidence is set out below.

The evidence

An international, multicentre study29 that randomised women seeking LARC to use of an ENG or LNG implant also had a non-randomised comparator group of Cu-IUD users. Similar percentages (31.3% of the 995 ENG-IMP users and 33.6% of the 971 Cu-IUD users) reported headache as a side effect on at least one occasion. No information is given as to the nature or frequency of headache. In integrated analysis of data from 11 manufacturer-sponsored phase II, III and IV clinical trials,28,85 headache was reported by 24.7% of the 942 subjects, but only 15.3% of subjects had headache that was considered to be related to or possibly related to use of the ENG-IMP. Headache was cited as a reason for discontinuation by only 1.6% of subjects.

More recently, amongst a cohort of 310 ENG-IMP users taking part in a manufacturer-sponsored prospective 3-year multicentre study, 18.6% reported headache (9% reported headache that was considered ENG-IMP-related).2

11.3 Acne

Key information

• C.  Observational studies suggest that during ENG-IMP use a minority of users experience new onset acne or worsening of existing acne while others have improvement in existing acne.

While a minority of subjects in observational studies reported new onset or worsening acne during ENG-IMP use, others experienced improvement in existing acne. The studies do not report severity or persistence of the acne reported during ENG-IMP use or use prior to study enrolment of hormonal contraception that could affect acne.

The evidence

In a comparative trial29 with a LNG implant, acne was reported by significantly more of the 995 women randomised to use of the ENG-IMP than by the 971 women in a non-randomised comparator group of Cu-IUD users (17.3% vs 13.1%, respectively).

A manufacturer-sponsored multicentre prospective cohort study of 635 women using the ENG-IMP over 2 years asked subjects about acne symptoms at baseline and at the end of the study. Some 12.8% reported an improvement in acne during implant use and 12.6% reported new onset or worsening of acne.18 Amongst 231 subjects in a manufacturer-sponsored American cohort study53 who reported no acne at baseline, 84% reported no change and 16% reported acne during ENG-IMP use; of the 84 subjects with acne at baseline, 61% reported an improvement, 31% no change and 8% worsening acne. Some 1.5% of all participants cited acne as a reason for discontinuation. In integrated analysis that included data from these studies, 11.8% of the 942 ENG-IMP users reported acne that was considered to be due to the implant, and 1.3% discontinued use because of acne.28,85

More recently, a manufacturer-sponsored multicentre study2 of 301 ENG-IMP users reported acne that was potentially implant-related in 12.3% of participants; 4% cited acne as a reason for discontinuation.

11.4 Depression

Key information

• C.  The available evidence is too limited to confirm or exclude a causative association between ENG-IMP use and depression.

The evidence

Amongst 942 new users of the ENG-IMP in manufacturer-sponsored phase II and III trials, 3.5% reported depression that was considered to be associated (or potentially associated) with use of the implant.85 Some 1% of these women cited depression and 2.3% cited emotional lability as their reason for discontinuation of the implant.28

A 2018 systematic review of studies that used externally validated measures of depression113 concluded that the identified data did not support a clear, general association between progestogen-only contraceptives and depression scores or incident depression diagnoses.

A study using data from Danish national databases114 reported significantly greater risk of first use of antidepressant medication for women using a progestogen-only implant compared with women who had not recently used hormonal contraception (RR 2.1; 95% CI 2.01–2.24); the study included 28 867 woman-years of implant use. In a second database study the same authors reported significantly greater risk of first suicide attempt amongst young Danish women using the progestogen-only implant than non-users of hormonal contraception.115 An earlier Swedish prescription database study116 that included 17 860 implant users aged 16–31 years reported an odds ratio for use of antidepressant medication of 1.69 (95% CI 1.61–1.77) for users of the ENG-IMP compared with non-users of hormonal contraception. In all these studies significant confounding factors cannot be excluded and causative association is not established.

11.5 Weight change

Key information

• C.  The available evidence is too limited to confirm or exclude a causal association between ENG-IMP use and weight gain.

The evidence

In 2019, the FSRH CEU systematically reviewed the evidence relating to use of the ENG-IMP and weight change to support the FSRH statement ʻContraception and weight gainʼ.117 Studies identified compared weight change in ENG-IMP users with Cu-IUD users; none of the studies included non-users of contraception as a comparator. Weight change varied widely between individual women in the studies, but on average women gained weight during use of both the ENG-IMP and the Cu-IUD. Most studies reported no statistically significant difference in weight change between the methods.

A 2017 prospective cohort study118 comparing 33 ENG-IMP, 85 LNG-IUS and 31 Cu-IUD users found that changes in body composition and weight did not significantly differ among those who continued their method for 12 months. Weight increases were 0.1, 0.5 and 0.4 kg, respectively; the difference between these was not statistically significant (p=0.97). The study used validated measures of eating behaviour and body composition and adjusted for confounding. An earlier analysis of this cohort119 evaluating weight gain over 12 months as the primary outcome found that ENG-IMP use (n=130) was not associated with significantly greater weight increase when compared to Cu-IUD use (n=100) (2.12 kg for ENG-IMP and 0.16 kg for Cu-IUD; the difference was not statistically significant). One study70 of body composition changes over 12 months among 23 ENG-IMP and 25 Cu-IUD users found that ENG-IMP users compared with Cu-IUD users had statistically significant increases in body weight (+4.1 vs −0.1 kg) and fat mass (+2.4 vs 0.2 kg). This study was, however, limited by very high losses to follow-up and no adjustment for possible confounding factors.

11.6 Other side effects

Integrated analysis of data from 942 women in 11 manufacturer-sponsored phase II, III and IV clinical trials85 records the following side effects that could potentially relate to ENG-IMP use: mastalgia (10.2% of subjects), abdominal pain (5.2%), dizziness (4.9%), emotional lability (5.7%), nervousness (3.5%) and nausea (2.5%).

12.1 Starting the etonogestrel implant at the beginning of a natural menstrual cycle

In line with manufacturer instructions,5 it is established practice that the ENG-IMP can be inserted on days 1–5 of a natural menstrual cycle without the need for additional contraceptive precautions (see Table 2).

12.2 Starting the etonogestrel implant after day 5 of a natural menstrual cycle

After day 5 of the natural menstrual cycle, the ENG-IMP can be quick started if a pregnancy test is negative (or it is certain that there has been no UPSI), even if very early pregnancy cannot be absolutely excluded because of UPSI in the last 21 days. Additional contraceptive precautions (eg, condom use) should be advised for the first 7 days of ENG-IMP use and a follow-up pregnancy test taken if appropriate. From the very limited available evidence there is no indication that use of the ENG-IMP in very early pregnancy is associated with adverse pregnancy outcomes. See FSRH Clinical Guideline Quick Starting Contraception48 and also Table 2.

For guidance when quick starting the ENG-IMP after oral EC see Section 12.7.

12.3 Starting the etonogestrel implant after childbirth

The ENG-IMP can be inserted at any time after childbirth including immediately after delivery.49 Contraception is required from day 21 after childbirth. If the ENG-IMP is inserted by day 21 after delivery it will be effective immediately with no requirement for additional contraception. If the ENG-IMP is quick started on day 21 or later, unless the criteria for lactational amenorrhoea are met, risk of existing pregnancy should be assessed prior to insertion and additional contraception (eg, condom use) is required for 7 days after insertion. See FSRH Clinical Guideline Contraception After Pregnancy49 and also Table 2.

12.4 Starting the etonogestrel implant after abortion

The ENG-IMP can be safely started at any time after medical or surgical abortion.49 The evidence indicates that the ENG-IMP can be inserted at the time of mifepristone administration without affecting the effectiveness of medical abortion.49 If the ENG-IMP is initiated at the time of abortion or within 5 days after abortion it will be effective immediately with no requirement for additional contraception. If quick started thereafter, risk of existing pregnancy should be assessed prior to insertion and additional contraception (eg, condom use) is required for 7 days after insertion. See FSRH Clinical Guideline Contraception After Pregnancy49 and also Table 2.

12.5 Switching to the etonogestrel implant from another contraceptive method

Evidence is lacking for maintenance of contraceptive effect when switching from other hormonal contraception to the ENG-IMP. Established FSRH guidance is given in Table 3. This may be more cautious than advice given in the SPC for Nexplanon.5 For switching from a Cu-IUD see Table 2.

12.6 Replacing the etonogestrel implant

Established FSRH guidance is given in Table 4.

12.7 Starting the etonogestrel implant after oral emergency contraception

The ENG-IMP can be inserted immediately after LNG-EC. Additional contraception (eg, condom use) is required for 7 days after insertion and a pregnancy test should be taken 21 days after the last UPSI.

Insertion of the ENG-IMP should be delayed for 5 days after UPA-EC to avoid affecting the effectiveness of the UPA-EC. Additional non-hormonal contraception (eg, condom use) is required until the implant is inserted and then for a further 7 days. A pregnancy test is required 21 days after the last UPSI. See FSRH Clinical Guideline Emergency Contraception46 and also Table 5.

14.1 What is the safest insertion site?

Robust clinical data do not exist to inform which Nexplanon insertion site is, in clinical practice, associated with lowest risk of accidental deep insertion, difficult removal, neurovascular injury and intravascular insertion.

The evidence

A recent manufacturer-funded study122 involving dissection of cadaveric arms was carried out to identify the insertion site at which there were fewest underlying neurovascular structures and thus least theoretical likelihood of neurovascular damage or intravenous insertion.

Dissection of the whole medial upper arm demonstrated smaller, less prominent neurovascular structures posterior to the sulcal line than anterior to it. On that basis the assumption was made that neurovascular injury is less likely with insertion posterior to the sulcal line. (The sulcal line is defined as the groove between the brachialis/biceps anteriorly and the triceps posteriorly.)

Multiple dissection windows were opened over triceps in 40 female cadaveric arms to identify underlying neurovascular structures in the subcutaneous tissue and deep fascia. With the arm abducted to 90°, the elbow flexed and the hand behind the head, no neurovascular structures were identified in an area 8–10 cm proximal to the medial epicondyle along the sulcal line and 3–5 cm posterior to the sulcal line. In contrast, significant neurovascular structures were present in dissection windows closer to the medial epicondyle and to the sulcal line. It was noted that flexing the elbow moved the ulnar nerve anteriorly, towards the sulcus and away from the implant insertion site, thus potentially reducing risk of injury.

GDG conclusions

On the basis of this evidence and to align guidance with that of the manufacturer, the GDG makes the following recommendations about insertion site:

• ▸  During insertion, the individual should lie on their back with their arm abducted to 90°, the elbow flexed and the hand behind the head.

• ▸  To identify the insertion site, the HCP should:

• ▸  Ask the individual to tense the biceps and the triceps muscles to allow palpation of the sulcus (the muscles can then be relaxed).

• ▸  Start at the medial epicondyle and measure 8–10 cm proximally along the sulcal line.

• ▸  From this point, measure 3–5 cm posteriorly, perpendicular to the sulcal line, to identify the insertion site (over triceps muscle).

• ▸  Pierce the skin with the implant introducer at this point and advance the introduction needle proximally just under the skin, parallel to the sulcal line.

See diagrams included in the Nexplanon package insert, diagrams in the SPC for Nexplanon5 and video (insertion and removal) online at www.nexplanonvideos.eu. 123

• ▸  After insertion, the presence of the implant under the skin should be confirmed by palpation of both ends. If the implant cannot be palpated it may not have been inserted, or could have been inserted too deeply. Check the insertion device and to ensure that the implant has been deployed, check the surrounding clinical area for the implant and see Section 19 (Management of impalpable implants) for further guidance.

14.2 Insertion site in existing users

An individual who has an expired ENG-IMP in situ at another site should have that implant removed and the new implant inserted at the new recommended site. If the expired implant is already in the new recommended position, it is established practice that the new implant can be inserted through the removal incision and advanced along a fresh adjacent track. There is not, however, study evidence to inform whether outcomes are any different with this approach than if the new implant is inserted close by through intact skin.

14.3 Nexplanon insertion procedure

There is little published evaluation of specific Nexplanon insertion and removal techniques; both practice and expert opinion vary. Procedures described in this guideline are based on the opinion and experience of the GDG and are intended as a guide to good practice, but are not evidence-based.

See Appendix 2 (Suggested Nexplanon insertion procedure).

14.4 Advice after etonogestrel implant insertion

After ENG-IMP insertion, users should be provided with the following information:

• ▸  Any requirement for additional contraceptive precautions and follow-up pregnancy testing

• ▸  Instructions for dressing removal, wound care and removal of paper sutures

• ▸  Likelihood of initial discomfort and bruising

• ▸  Signs of local infection and how to access review if infection is suspected

• ▸  How to feel for the implant after removal of the wound dressing (the implant should always be palpable – all users should be advised to seek review if at any time they cannot feel their implant)

• ▸  How to access review of adverse effects and implant removal services

• ▸  When to attend for replacement.

The GDG recommends that routine follow-up by a HCP is not required during the 3 years of licensed use of an ENG-IMP.

15.1 When can the etonogestrel implant be removed?

The ENG-IMP should generally be removed if it has been in situ for the 3 years of licensed use. The ENG-IMP can be removed at the user’s request at any time within 3 years after insertion without the need for abstinence or use of additional contraception prior to removal. If the individual does not wish to become pregnant, alternative contraception is required as soon as the implant has been removed.

15.2 Switching from the etonogestrel implant to another method of contraception

See Table 6 and Table 7 for guidance when switching from the ENG-IMP to another method of contraception.

In general, the ENG-IMP should be removed when it is no longer effective for contraception. This includes implants that are deeply sited or impalpable (these cases should be referred to specialist deep implant removal services). If an individual does not wish to have their ENG-IMP removed after 3 years the GDG recommends that they should be made aware that:

• ▸  The implant is likely to continue to have an effect on fertility for a considerable time.

• ▸  Limited evidence suggests the risk of pregnancy in the fourth year of use of an ENG-IMP is likely to be very low.

• ▸  Contraceptive effectiveness after 4 years of use of the ENG-IMP is unknown.

• ▸  Studies have not assessed whether indefinite retention of an expired ENG-IMP is associated with any adverse effect.

• ▸  There is inadequate evidence to inform whether there is any risk associated with presence of an expired ENG-IMP during pregnancy.

After discussion, some individuals may make an informed decision to leave their ENG-IMP in situ indefinitely.

An ENG-IMP that is in the upper arm but is not in the position recommended by current guidance should not be removed solely because of its position.

15.3 Standard etonogestrel implant removal procedure

ENG-IMPs should only be removed by HCPs who have undergone formal training in ENG-IMP removal technique. It is noted that there is little published evaluation of specific Nexplanon insertion and removal techniques and that practice and opinion vary. Procedures described in this guideline are based on the opinion and experience of the GDG and are intended as a guide to good practice, but are not evidence-based.

See Appendix 3 (Suggested standard Nexplanon removal procedure).

15.4 Advice after etonogestrel implant removal

After etonogestrel implant removal, users should be provided with the following information:

• ▸  Potential fertility from time of implant removal

• ▸  Any requirement for additional contraceptive precautions and follow-up pregnancy testing

• ▸  Options for (and access to) ongoing contraception unless a further subdermal implant has been inserted

• ▸  Wound care

• ▸  Likelihood of initial discomfort and bruising

• ▸  Signs of local infection and how to access review if infection is suspected

• ▸  When to remove any paper sutures.

The GDG recommends that routine follow-up by a HCP is not required after ENG-IMP removal or replacement.

16.1 Lidocaine 1%

Lidocaine 1% is the accepted standard local anaesthetic for implant insertion and removal. It may be used with or without adrenaline 1:200 000 (adrenaline may reduce local bleeding). The syringe plunger should be drawn back prior to the injection to reduce risk of accidental intravenous administration. The skin should be infiltrated at the point of insertion; some clinicians choose also (in line with manufacturer guidance) to infiltrate along the insertion track, although there are no pain receptors in the subdermal layer. A maximum of 2–3 ml of 1% lidocaine is required.

16.2 Ethyl chloride spray

Ethyl chloride spray is an inexpensive vapocoolant that by cooling the skin and reducing impulses in local sensory nerves produces a local anaesthetic effect of rapid onset but short duration of action. The GDG considers that ethyl chloride spray is a good alternative to lidocaine for implant insertion procedures where the skin is not affected by conditions such as eczema or broken prior to the procedure. Care must be taken to follow manufacturer instructions to avoid over-cooling of the skin. Ethyl chloride spray may be of particular benefit for individuals who wish to avoid needles and those with lidocaine allergy. The insertion procedure needs to be performed quickly after application as the anaesthetic effect is of short duration (about 60 seconds). This makes ethyl chloride less suitable for implant removal procedures, but its use may be considered by individual HCPs.

The evidence

A 2016 Cochrane review124 of RCTs that compared ethyl chloride spray and similar vapocoolants to placebo or no anaesthesia at the time of venous cannulation concluded that ethyl chloride application itself was associated with mild discomfort, but that it reduced the pain associated with the procedure. No serious adverse events were reported.

A small study125 of use of ethyl chloride spray for ENG-IMP insertion reported that staff found use of ethyl chloride spray straightforward and that anaesthesia was adequate, without reported adverse side effects. The authors reported a projected cost saving compared with use of lidocaine. Larger studies would be required to ascertain whether the vapocoolant effect and the necessarily rapid insertion procedure have any impact on correct insertion.

17 Implant insertion and removal in anticoagulated individuals, those with inherited bleeding disorders and people with low platelet count

Both ENG-IMP insertion and standard ENG-IMP removal are minor procedures with minimal risk of significant bleeding (similar to that associated with minor dermatological procedures, dental extraction and cardiac pacemaker implantation).126,127 Local haemostasis is likely to be achieved by application of wound site pressure. The risk of significant bleeding associated with these procedures in individuals using warfarin (with a stable international normalised ratio (INR)), direct-acting oral anticoagulants, low molecular weight heparin or antiplatelet drugs is likely to be low. In contrast, there is a risk of thrombosis if anticoagulants are stopped, which could in some cases have life-threatening consequences.

Warfarin,126 direct oral anticoagulants,126,128 low molecular weight heparin and antiplatelet drugs129 should generally not be stopped for ENG-IMP insertion or standard removal. For individuals using direct oral anticoagulants or low molecular weight heparin, procedures should be scheduled to coincide with the lowest anticoagulant effect; for example, if the dose is taken daily in the evening, insertion in the afternoon would carry a lower bleeding risk than insertion in the morning. Non-steroidal anti-inflammatory drugs for pain relief should be avoided in the periprocedure period to avoid increased risk of bleeding.

Expert opinion suggests that a platelet count >50x109/L is adequate for standard ENG-IMP insertion and removal procedures.

For individuals with inherited bleeding and platelet disorders and platelet count <50x10⁹/L, management of bleeding associated with implant insertion and removal procedures should be discussed with the haematologist on an individual basis.

See FSRH CEU Statement Management of women taking anticoagulants or antiplatelet medications who request intrauterine contraception or subdermal implants.130

18.1 Implant migration

Key information

• D.  Cases of local migration of the ENG-IMP have been reported.

• D.  Rare cases of intravascular insertion of the ENG-IMP and subsequent distant vascular migration have occurred.

Clinical recommendations

• ✓  Individuals considering use of the ENG-IMP should be advised that intravascular insertion and distant migration are rare complications of the Nexplanon insertion procedure.

• ✓  ENG-IMP users should be advised to feel for the implant in their arm once the insertion wound has healed to check that it is in situ. If they cannot feel their implant at any time, users should have its presence confirmed by an HCP.

• ✓  HCPs should consider the possibility of implant migration if the implant is not palpable near to the insertion site.

The evidence

Local and non-vascular migration. Evidence from an observational study that followed up 100 Implanon insertions (over biceps) suggests that if inserted correctly, migration of the implant from the insertion site was typically less than 2 cm.132 There are, however, case reports of greater local migration.

Literature review identifies a small number of case reports of local migration of ENG-IMP 6–12 cm from their insertion site towards the axilla.133–139 In addition, Kang et al140 reported 11 cases of ENG-IMP migration to the axilla, one to the chest wall, two to the region of the clavicle/“neck line” and one to the shoulder region. These cases (from various countries) had been reported to the United States Food and Drug Administration (FDA) adverse event reporting system and had not been reported elsewhere in the literature.

Distant vascular migration. Rare cases have been reported of intravascular ENG-IMP insertion with subsequent distant vascular migration (usually to the pulmonary vasculature). Data held by the manufacturer suggest that worldwide there is one case of intravascular migration for every 1.3 million implants sold.120 Other estimates differ, however. A survey141 of French physicians identified 12 cases of Nexplanon migration to the pulmonary vasculature between January 2012 and July 2017. In the same period, French databases recorded insertion of 1.2 million Nexplanon implants. This suggests a rate of Nexplanon migration to the pulmonary vasculature of 1 in 100 000. There may be additional unrecognised or unreported intravascular insertions. It is noted that (unlike in the UK) in France there is no requirement for formal training in Nexplanon insertion.

International case reports142–158 describe intravascular migration of 17 ENG-IMP (both Implanon and Nexplanon) to the pulmonary vasculature after presumed insertion into veins in the upper arm. Kang et al140 reported nine and Ohannessian et al141 reported seven additional cases of implant migration to the pulmonary vasculature.

In some cases subjects reported significant local haematoma at the time of insertion, or later cough, chest pain or dyspnoea; others were asymptomatic. After establishing the absence of the implants from both arms, Nexplanon implants were located using X-ray and/or computed tomography (CT) scan. Many of the implants were retrieved from the pulmonary vasculature endovascularly; a few required thoracoscopy, and some individuals opted to leave the devices in situ.

One case of distal embolisation of an implant inserted into the brachial artery is reported, with initial profuse bleeding at the time of insertion and symptomatic distal arterial occlusion a few days later.159

GDG conclusion

The GDG recommends that individuals considering ENG-IMP insertion should be made aware that intravascular insertion and distant migration are rare complications of the insertion procedure. Users should be advised to feel for their implant once the insertion wound has healed to check that it is in situ and to seek review by an HCP if they cannot feel the implant. It is noted that while some individuals with intravascular insertion reported associated symptoms including excessive bruising or haematoma at the insertion site, dyspnoea and cough, others were asymptomatic.

For management of non-palpable implants see Section 19. Cases of implant migration should be managed by specialist sexual and reproductive healthcare (SRH) services according to local protocols. All cases should be reported to the manufacturer and to the Medicines and Healthcare products Regulatory Agency (MHRA) so that accurate data can be collected.

18.2 Local reaction

Implant site pain during ENG-IMP use was reported by around 3%-5% of users, and local haematoma by about 2% of users in manufacturer-funded observational studies.2,28,85

Case studies160–167 have described a small number of individual cases of local erythema, swelling, itch and pain, sometimes with purulent discharge, fractured implant or eruption of the implant through the skin. Some cases occurred soon after insertion, others after a significant interval and recurrence with subsequent implants has been described. Authors variously attribute these local reactions to infection or allergy (possibly, it has been suggested, to barium). Variable response to treatment with antibiotics and/or antihistamine has been reported. Personal correspondence from specialist implant removers describes similar cases, many requiring removal of the implant to achieve resolution, despite use of antibiotics.168

There is no clear evidence-based approach to such cases. The GDG suggests that early intervention with antibiotics/incision and drainage is appropriate if infection is suspected and that removal should be considered, certainly if the implant has erupted through the skin.

18.3 Nerve damage

Case studies describe cases of neuropathy (most affecting the ulnar nerve) associated with ENG-IMP insertion169–173 and injury to the median, cutaneous and ulnar nerves associated with ENG-IMP removal; in some cases, lasting loss of sensory and motor function is reported.174–182 Robust data to inform incidence do not exist, as cases are not reliably reported and recorded.

18.4 Intramuscular insertion

Case studies describe individual cases of intramuscular insertion of ENG-IMP and removal of ENG-IMP from muscle.183–186 Robust data to inform incidence do not exist, as cases are not reliably reported and recorded.

19.1 Initial management of impalpable implants

No attempt should be made to remove an impalpable implant that has not been localised. After checking that the ENG-IMP cannot be felt in the other arm, a pregnancy test should be taken, and advice given to use additional contraception until the presence of the implant is confirmed. Further investigation should be decided in consultation with local specialist SRH services according to their protocol. Initial investigation may include localisation of the implant by X-ray of the arm (note that Implanon is not radio-opaque) or by ultrasound using a high-frequency linear array transducer (10 MHz or greater).

19.2 Etonogestrel implants that have been identified deeply sited in the arm

Contraceptive effectiveness. Studies have not specifically considered the contraceptive effectiveness of an ENG-IMP that is in the arm, but sited more deeply than subdermal. In practice, however, it is generally considered that a user may rely on a deeply sited ENG-IMP (that has been confirmed to be present) for contraception for 3 years after insertion.

Referral should be made to specialist services for removal after 3 years of use, or at the request of the user. Some individuals may opt to leave a deeply sited implant in situ indefinitely to avoid risk associated with removal (see Section 15.2). It is noted that a retained implant is likely to continue to have an effect on fertility for a considerable (but unknown) time after expiry.

Removal. To minimise risk of neurovascular damage, removal of an ENG-IMP that is impalpable or difficult to palpate should only be attempted after it has been localised in the arm, and then only by a practitioner trained and experienced in complex implant removal techniques, usually with ultrasound guidance187–193 (fluoroscopic guidance has also been described184,187). Various techniques for removal of deeply sited implants are described in the literature;184,187,189,194–197 there is no clear evidence as to which technique is safest or most effective; choice of method will often depend on implant location. Description of such specialist techniques is beyond the scope of this guideline.

19.3 Etonogestrel implants that are not identified in the arm

If, after appropriate imaging, the ENG-IMP is not identified in the arm, further investigation by specialist services may include serum ENG assay and imaging of the chest – chest X-ray/CT/CT pulmonary angiography according to local protocol.142–157 Case studies report both percutaneous and endovascular retrieval of implants from the pulmonary vasculature as well as implants left in situ.142–157

20.1 Removal of broken etonogestrel implants

There is no agreed standard technique for removal of a broken ENG-IMP. The GDG suggests that removal through an incision over the site of breakage of an implant that is broken into two pieces may allow removal by a ‘pop-up’ technique from each end through a single incision. However, clinical judgement is required in individual cases. After removal, the implant should be checked and measured to ensure that the entire 4 cm device has been removed.

If an implant is damaged it is recommended that the problem is reported to the manufacturer and the MHRA Yellow Card scheme.208