Long-acting reversible contraceptive (LARCs) methods

Journal Pre-proof Long-acting reversible contraceptive (LARCs) methods Luis Bahamondes, Arlete Fernandes, Ilza Monteiro, M. Valeria Bahamondes

PII:

S1521-6934(19)30178-6

DOI:

https://doi.org/10.1016/j.bpobgyn.2019.12.002

Reference:

YBEOG 1995

To appear in:

Best Practice & Research Clinical Obstetrics & Gynaecology

Received Date: 2 October 2019 Revised Date:

4 December 2019

Accepted Date: 10 December 2019

Please cite this article as: Bahamondes L, Fernandes A, Monteiro I, Bahamondes MV, Longacting reversible contraceptive (LARCs) methods, Best Practice & Research Clinical Obstetrics & Gynaecology, https://doi.org/10.1016/j.bpobgyn.2019.12.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.

1 Long-acting reversible contraceptive (LARCs) methods Luis Bahamondes1, Arlete Fernandes1, Ilza Monteiro1, M. Valeria Bahamondes2

1

Department of Obstetrics and Gynecology, University of Campinas Faculty of Medical

Sciences (UNICAMP), Campinas, SP, Brazil 2

Consultant, Centro Latinoamericano de Perinatologia, Salud de la Mujer y

Reproductiva, Montevideo, Uruguay.

Corresponding author Luis Bahamondes Caixa Postal 6181 13084-971 Campinas, SP, Brazil Tel: 55-19-3289-2856 Fax: 55-19-3289-2440 E-mail: [email protected]

2 Abstract

Unplanned pregnancy (UP) is a public health problem which affects millions of women worldwide. Providing long-acting reversible contraceptive (LARC) methods is an excellent strategy to avoid or at least reduce UP, because the effectiveness of these methods is higher than for other methods, and is indeed comparable to that of permanent contraception. Since the initial introduction of the inert plastic intrauterine device (IUD) and of the six-rod implant, pharmaceutical companies have introduced a copper IUD (Cu-IUD), different models of levonorgestrel-releasing intrauterine systems (LNG IUS), and one and two-rod implants, which certainly improved women’s LARC options. The main characteristic of LARCs is that they provide high contraceptive effectiveness with a single intervention, and that they can be used for a long time. Emerging evidence from the last few years has demonstrated that it is possible to extend the use of the 52mg LNG IUS and of the etonogestrel-implant beyond the five- and three-years, respectively, which adds new value to these LARCs.

Key words: contraception; long acting contraceptives; copper intrauterine device; levonorgestrel-releasing intrauterine system; subdermal implants, LARCs

3 Introduction Unplanned pregnancies (UPs) or mistimed pregnancies are one of the major health problems worldwide because they are associated with increased maternal and infant morbidity and mortality social burden and social costs. High rates of UPs persist despite the increasing rates of modern contraceptive method use, including among adolescent girls [1]. UPs occur in the context of lack of contraceptive use, improper use, method failure, or lack of access to services including contraceptives. All women should receive contraceptive counselling and should have access to their contraceptive method of choice at an affordable cost. The Pearl Index (PI) is a measure used in clinical trials to describe contraceptive effectiveness. It is defined as the number of pregnancies which occurred throughout the trial divided by the number of cycles during which the product was tested, and the n multiplied by 1300. In addition, it is common to distinguish contraceptive effectiveness with “typical use” from that with “perfect use” during clinical trials, as these can differ. “Typical use effectiveness” reflects real life use and accounts for inconsistent or incorrect use. It is therefore considered by many researchers to be the most clinically relevant measure of contraceptive effectiveness. However, “perfect use effectiveness” is what is measured during a research study or clinical trial and it measures contraceptive efficacy more directly [2].

Among users of the long-acting reversible contraceptive (LARC) methods, there is no difference between typical and perfect use because these contraceptive methods do not require any user action after insertion, which means the user cannot alter the method’s efficacy. David Grimes calls these methods, which require attention no more frequently than every three years, “forgettable contraceptives” [3]. LARCs include various models of the copper-bearing intrauterine device (Cu-IUD), several models of

4 the levonorgestrel-releasing intrauterine system (LNG IUS), and the subdermal implants.

The contraceptive failure rate of LARC methods is very low. The cumulative pregnancy rate in the first 3 years is 0.9/100 woman-years (W-Ys), which is significantly lower when compared to that of short-acting contraceptive (SARC) methods (patch, vaginal ring or combined oral contraceptives). Also, the contraceptive effectiveness of LARCs is independent of user characteristics such as parity and age [4]. Contraceptive effectiveness is influenced by compliance, continuation rate, fecundity and frequency of coitus [3]. The high contraceptive effectiveness of LARC is in part due to the fact that many behaviour related variables that affect compliance are removed. SARC method users have significantly higher rates of UP during the first year of typical use. Whereas the one-year pregnancy rate for typical use is less than 1/100 W-Y for LARCs, it is 6/100 W-Y for depot-medroxyprogesterone acetate injection and 9/100 W-Y for combined oral contraceptive pills, progestin-only pills, the patch or vaginal ring; these are all methods which require user involvement [4]. In addition, adolescents and young women (less than 21 years old) who use SARCs have significantly higher contraceptive failure rates than older women [4]. Intrauterine contraceptives (IUCs) Intrauterine contraceptives (IUCs) include the various models of the copperbearing intrauterine device (Cu-IUD) and of the levonorgestrel-releasing intrauterine system (LNG IUS). We like to state that many of the recommended strategies reported are off label use, and are not yet included in many guideline recommendations from international or national bodies.

5 The copper-bearing intrauterine device (IUD) In 1988, the US Food and Drug Administration (US FDA) approved the most highly effective copper-bearing IUD, the TCu380A. It is a T frame device with a 380mm copper surface distributed across its two arms. Currently, it is the most commonly used IUD worldwide [5]. The TCu380A IUD is labelled by most of the national health authorities as being effective for up to 10 years. However, there is strong scientific evidence showing that the same device can be maintained for more than 10 years, mainly among women over 35 years old. In fact, many Health Providers routinely recommended keeping the same device until menopause [6]. In clinical practice, women who received a TCu380A IUD over the age of 25 may be able to keep the same device up to menopause, or almost 25 years of continuous use without changing the device. Although worldwide there are many models of copper-bearing IUDs, one review about Cu-IUDs [7] found that the TCu380A IUD was more effective than other CuIUDs. However, many of the reviewed studies were conducted only among parous women. Rates of expulsion and removals due to bleeding and pain are similar for all models of Cu-IUDs.

Mechanism of action of different IUCs Many Health Providers still believe that IUCs exert their contraceptive action as abortifacient devices, and that they prevent the implantation of fertilised ova. However, in 1987, the WHO stated that “The IUDs exert their antifertility effects beyond the uterus and interfere with steps in the reproductive process that take place before the ova reach the uterine cavity.” [8,9] Furthermore in classic studies [10] the authors were unable to obtain fertilised ova in the Fallopian tubes of women with IUDs in situ, and concluded that the mechanism of action of IUDs is unlikely to involve the destruction of

6 existing embryos or the prevention of implantation [10-12]. In fact, it is now known that the main mechanism of action of copper-IUDs is spermicidal action via the development of a local sterile inflammatory process induced by the presence of a foreign body in the uterus [13,14]. However, the mechanism of action of the existing models of the LNG IUS, independently of the daily release of LNG, is primarily the thickening of cervical mucus and impaired sperm penetration [15,16]. Ovulation is suppressed but at different rates according to the daily LNG release rate. Also, it is important to note that the local LNG effect is more significant than the systemic once because the levels of LNG in the endometrium are 1,000-fold higher than in the serum. Contraceptive effectiveness The contraceptive failure rate for most of the Cu-IUDs (mainly based on studies of the TCu380A IUD), is one of the highest among LARC methods [6-8,17]. The reported contraceptive failure rates ranges from 0.1 to 2.2/100 women-years (W-Ys) [7]. One frameless Cu-IUD (GyneFix) was designed to reduce bleeding complaints and expulsions and the World Health Organization (WHO) conducted a study for up to 8 years in which they compared the TCu380A to this new model [17]. A total of 2,027 and 2,036 women were randomised to the frameless IUD or the TCu380A IUD, respectively. Cumulative pregnancy rates were 1.2 (95% CI: 0.7-1.9) and 2.5 (95% CI: 1.8-3.4) for the frameless Cu-IUD and TCu380A, respectively, up to the eighth year of use. A multicentre study conducted by the WHO compared the contraceptive effectiveness of the TCu380A IUD to that of the MultiLoad 375 IUD (MLCu375) with 375 mm of copper. The contraceptive failure was significantly lower for the TCu380A up to 10 years, with a rate difference (RD) of 1.9% (95% CI 0.12–3.59%) [18]. Other authors reported the findings from a large study titled “European Active Surveillance Study for Intrauterine Devices” (EURAS IUD), which was conducted in

7 six European countries. They followed 61,448 new users of more than 30 different models of Cu-IUD who were enrolled by more than 1200 Health Providers [19]. They analysed data from 17,323 users with 17,703 W-Ys of observation. The most commonly used Cu-IUDs were NovaT (200 or 380; 37%), T Safe Cu380 (18%) and Multiload Cu (250 or 375; 14%). Only 12% of the participants were nulligravidas. The observed Pearl Index (PI) was 0.52 (95% CI: 0.42–0.64) with a life-table estimate of contraceptive failure for the first year of use of 0.63/100 W-Y. They compared PI according to the copper surface area of the different IUDs, and found a PI of 0.56 (95% CI: 0.24–1.09) for IUDs with a copper surface area > 300mm2 and of 0.62 (95% CI: 0.50–0.78) for those with a surface area <300 mm2. They also found a higher pregnancy rate among young women. The pregnancy rate (95% CI) was 1.35 (0.95-1.76) among women aged 18-29; 0.57 (0.37-0.77) among women 30-39; and 0.05 (0.0-0.12) among those 40 or older according to a life-table analysis. Different pregnancy rates according to copper surface area have also been reported by other authors. A Cochrane review which included randomised clinical trials (RCT) found PIs of 0.5–2.2 with a copper surface area of less than 300 mm,2 and of 0.11.0 when the copper surface was greater than 300 mm2 [7,20,21]. Also, the authors of another large clinical trial found a PI of 0.3–1.3 among users of the TCu380Ag IUD, which has silver in addition to copper in the vertical arm [22]. Cu-IUDs have low overall pregnancy rates and also very low ectopic pregnancy rates. In one study, these ranged from 0.08–0.8/100 W-Y [23]. In one study, the Hazard Ratio (HR) of ectopic pregnancy among Cu-IUD users compared to non IUD users was 0.20 (95% CI: 0.08–0.48), and did not change after adjustment for age, body mass index (BMI; kg/m2) and parity (HR 0.26; 95% CI: 0.10–0.66) [21]. Although the use of any IUC or any other modern contraceptive use reduces the rates of ectopic

8 pregnancy compared to no contraceptive use, it is important to note that in the rare cases of pregnancy with an IUC in situ, the probability of an ectopic pregnancy is relatively high. Use of Cu-IUD among nulligravidas and adolescents Many Health Providers are concerned about IUC use among adolescents and nulligravidas. This concern initially arose from the misconception that IUCs caused pelvic inflammatory disease and consequently future infertility [24]. Also, when the TCu380A IUD was initially introduced in the US, the product label included a statement that the “…device is recommended for women with one child. . .”.

Since

then, the USFDA, the WHO and many international agencies have approved and even recommended the use of IUC in this population. Currently, they do not make any restrictions to the use of IUC by adolescents and nulligravid women [25]; although it is still being debated [26,27]. However, there is evidence that the use of LARC reduces UP among adolescents [28].

Immediate postpartum IUC use In the last few years, there has been great interest in increasing LARC use in many settings, including immediately postpartum. This practice is justified because evidence shows that many women never return to the obstetric service to receive any contraceptive method. This is especially true among populations who live far from health facilities or who have travel costs or time constraints. Yet the return of fertility can occur as soon as 4 weeks after delivery [29]. The WHO recommends that women wait at least 24 months after childbirth before attempting a new pregnancy in order to avoid an increased risk of maternal and infant morbidity and mortality [30]. Both the Cu-IUD and LNG-IUS can be safely inserted in the immediate postpartum period

9 (within the first 48 h of delivery) [31]. This practice allows women to receive the contraceptive method pf their choice before leaving the obstetric facility [32]. PPIUD insertion is a simple procedure associated with few complications, as uterine perforation and infection rates are extremely low [33]. The WHO, the Centres for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynaecologists [25,34,35] all endorse immediate PPIUD insertion and immediate postpartum insertion of contraceptive implants. Though the procedure for PPIUD insertion is safe and easy, expulsion rates are higher when compared to interval insertions (after 42 days after childbirth) [34]. Expulsion after postpartum placement may decrease effectiveness and put women at risk of an UP. They can also increases the method’s cost due to the cost of replacement device; however, the high continuation rates after immediate PPIUD insertion outweigh the risk and consequently the procedure is cost-effective [36]. One systematic review [36] examined PPIUD placement of both Cu-IUDs and LNG-IUS. Expulsion rates were lower for interval insertion compared to immediate PPIUD insertion (10 minutes postplacental) and early postpartum insertion (within 48 hours after childbirth). They were higher for vaginal delivery compared to Caesarean (C)-delivery and for the LNG-IUS when compared to the CuT380A IUD. The current recommendation is that women follow-up at least once in the first six months after PPIUD insertion, so that any inadvertent expulsion can be detected. Also, in terms of timing, we now know that PPIUD placement within 10 minutes after placental delivery is ideal [36].

Main reasons for discontinuation for Cu-IUD

10 One of the concerns of Health Providers when women discontinued prematurely the use of LARC methods is because users could opt for less effective contraceptive method. The worse reason for IUD discontinuation is pregnancy with an IUD in situ, which is rare but may occur (PI 0.52; 95% CI: 0.42–0.64) [19]. It is important to take into account that pregnancy with a Cu-IUD or a LNG IUS in situ is a risk factor for adverse pregnancy outcomes, including miscarriage (in some cases septic abortion), preterm labour, and chorioamnionitis [37]. When a pregnancy occurs with an IUD in situ the recommendation is to remove it if the strings are visible at the external cervical os. The common recommendation is to remove the IUD only if the strings are visible. Some authors have recommended ultrasound-guided removal when the strings are not visible [38], since they noted that the rates of spontaneous abortion and preterm birth may not increase after ultrasound-guided IUD removal [39]. However, even when the IUD is removed, there is an increased risk of complications compared to women who became pregnant without an IUD in situ [39]. The main medical reasons for Cu-IUD or the LNG IUS discontinuation are expulsions and complaints of bleeding and/or pain [40-43]. Some authors have found that nulligravidas and women with only one delivery have a trend towards higher expulsion rates compared to parous women; however, this issue is still being debated [44,45] because other authors did not find differences in expulsion rates [26,46,47]. Furthermore, in the past it was recommended that women have their IUC strings periodically checked [48]. However, in a study of 1612 women with a history of prior IUC expulsion, periodical visits to check IUC strings did not predict or reduce the risk of further IUC expulsions. Also, 52.3% of all IUC expulsions occurred in the first six months, and 42.9% occurred in the first three months after IUC placement [49].

11 One study conducted by the WHO [17] compared the frameless CuIUD (GyneFix) with the TCu380A IUD and showed that expulsion rates at the end of the first year of use were 5.3/100 W-Y (95% CI: 4.4-6.4) and 2.5/100 W-Ys (95% CI: 1.9-3.3) for the frameless IUD and the TCu380A IUD, respectively, without significant differences among groups. Expulsion rates between the TCu380A IUD and the MLCu375 IUD showed a trend towards significantly more expulsions with the MLCu375 [18]. In addition to expulsion or pregnancy the main reasons for Cu-IUD discontinuation are unfavourable bleeding patterns (reported as heavy and prolonged bleeding) and lower abdominal pain reported as cyclic and non-cyclic cramps. Cumulative removal rates of 14/100 W-Ys up to 10 years of use for these reasons have been described [6,22]. Despite the fact that Cu-IUD users have more bleeding, they do not have increased rates of anaemia, and removals for bleeding reasons may be highly influenced by women’s tolerability of side-effects and by Health Providers practices [36]. For many years, the prevalence of IUC use was low because of a concern about a causal relationship between Cu-IUD use and pelvic inflammatory disease (PID) and future infertility. This concern was one of the reasons why many Health Providers did not want to provide IUC to nulligravidas or adolescents. However, the association was weak and based on numerous confounders with poorly selected comparison groups. Today, the consensus is that there is no association between IUD use and infertility due to tubal occlusion. Rather, infertility is associated with reproductive tract infection, mainly Chlamydia trachomatis. The incidence of PID among IUD users is higher only for the first 20-30 days after IUD insertion, and this caused by pre-existing sexually transmitted infections rather than by the IUD in and of itself [50,51].

12 The main complication during or after IUC insertion is uterine perforation. It is important to clarify that perforation occurs at IUC insertion and could be total or partial. In the case of partial perforation, it could take a long time to discover the IUC in the abdominal cavity. One prospective cohort study [52] reported perforations up to 12 (61,448 users) and 60 (39,009 users) months after insertion among new users of the LNG IUS and Cu-IUD. The overall perforation rate was 2.1/1000 insertions (95% CI: 1.6-2.8) for LNG IUS users, and 1.6/1000 insertions (95% CI: 0.9-2.5) for Cu-IUD users. The main variables associated with perforation were breastfeeding (RR 4.9, 95% CI: 3.0-7.8) and time since delivery (RR 3.0, CI: 1.5-5.4). Overall, uterine perforation is rare, and the clinical sequelae of perforations are mild. The levonorgestrel releasing intrauterine system “family”

The first levonorgestrel intrauterine system (LNG IUS) which was released is a device which contains 52mg of LNG and released 20µg of LNG per day. Currently, there are several such commercial products on the market: Mirena®, Liletta®, Levosert® and Avibella®. They all have a high contraceptive performance with a pregnancy rate of 2/1000 women-years (WY) [53]. They are approved for use up to five years after device placement, but there is an increasing amount of scientific evidence demonstrating that they are effective for up to seven years [54]. The LNG release rate is 20µg/day immediately after device insertion, but this rate decreases over time to 10-12µg/day at five years of use. Serum levels are still detectable in the eighth year of use. For these devices, mean LNG serum levels (± SEM) decreased from 253 ± 27 pg/ml (range 86 to 760) during the first two months after insertion to 137 ± 12 (range 23 to 393) at seven years of use and 119 ± 9 pg/ml (range 110 to 129) at eight years of use [55,56]. The LNG IUS can be used by women who have contraindications to oestrogen use [2]. It also has many non-contraceptive benefits due to its

13 antiproliferative action on the endometrium, including reduced endometriosis-associated pain, dysmenorrhoea, and menstrual bleeding volume. This makes the LNG-IUS an excellent choice for the treatment for heavy menstrual bleeding (HMB) [57,58]. Smaller LNG IUSs have been introduced in many markets in the last few years. These were designed to facilitate device insertion and adaptation to nulligravid women and adolescents. They include Kyleena,® which has 19.5mg of LNG and is approved for up to five years of use, and Jaydess®/Skyla,® which has13.5 mg of LNG and is approved for up to three years of use [59]. A device called Femilis 60 (APCOR R&M, Belgium) also exists, which was developed to facilitate insertion. It has a simpler inserter compared to other conventional T-shaped devices, because the arms are folded down during the insertion process. Femilis Slim is similar but has a more flexible and thin design and has been recommended for use by postmenopausal women for endometrial protection when woman is under oestrogen continuous therapy [60]. Despite the fact that newer devices have lower LNG release rates, their contraceptive failure rates are similar to those of the 52mg LNG IUS. The reported rate for the new 19.5mg LNG IUS, which releases 17.5 µg/day and 7.4 µg/day at the first and the fifth years of use, respectively, is the same as for the 52mg LNG IUS. For the 13.5mg LNG IUS (Jaydess®/Skyla®), which releases 12µg/day and 5µg/day at the end of the first and third years of use, respectively, it is only slightly higher (0.4/100 W-Y) [61,62]. However, bleeding patterns differ significantly between the LNG IUS with different LNG doses. The rate of amenorrhoea at six months, for example, is 11% for the 52mg IUS; 5% for the 19.5mg IUS; and 3% for the 13.5mg IUS. The rate of

14 irregular bleeding at 12 months after insertion is 6% for the 52mg IUS; 17% for the 19.5mg IUS; and 23% for the 13.5mg IUS [63]. Expulsion rates are similar for the three LNG-IUS doses and are around 4.6%. Early discontinuation rates were also similar, as were the most common reasons for discontinuation: unfavorable bleeding patterns, acne and dysmenorrhea [64,65]. Other reported reasons for discontinuation are lower abdominal pain, breast tenderness, mood swings and dyspareunia. Importantly, the number bleeding and especially of spotting may initially increase after LNG IUS insertion; however, as the duration of use increases, the number of bleeding days decreases and more than 20% of women report amenorrhoea at the end of five years of use [66]. Due to the higher prevalence of unplanned pregnancies among adolescents, the use of LARC methods, including IUS, has been strongly recommended for this population. However, IUS use by adolescents remains infrequent worldwide [67,68]. One reason for this may be the high initial up-front cost of the devices. Another barrier is that many Health Providers continue to be concerned about the safety of IUS in this population [69]. Because LNG IUS are extremely effective, we have limited data on the outcomes of the few pregnancies that do occur with LNG IUS in situ. One study used a questionnaire and identified 40 pregnancies among17,360 users of the 52 mg LNG-IUS who used the devices over 58,600 W-Ys. The pregnancies were corroborated by reviewing medical records, and 63% of these were found to be ectopic pregnancies. Only 10/15 of the intrauterine pregnancies were continued and of these, eight ended in miscarriage, and two ended in uncomplicated full-term deliveries of healthy babies [70]. In a review that included manufacturer information and a case-series, congenital anomalies were described in 6% of 34 intrauterine pregnancies [71]. Unfortunately,

15 there is insufficient data to make any definitive conclusion about pregnancy outcomes with IUS in situ. Progestin-containing subdermal contraceptive implants

The main characteristics of contraceptive implants are the lack of oestrogen and the subdermal release of hormones, which bypasses hepatic metabolism [72]. Two new progestogen-releasing contraceptive implants have been used worldwide and, together with the Cu-IUD and LNG IUS, make up the LARCs methods. The etonogestrelreleasing implant (ENG-implant), with c3-keto-desogestrel (3-KSDG), is approved for use up to three years. It contains a very high potency progestogenic compound with reportedly more progesterone-like effects and less affinity for the androgen receptor than LNG [73]. The LNG-implant, on the other hand, is approved for up to five years, and it consists of two silicone rods that each contains 75 mg of LNG.

Mechanism of action of subdermal implants The ENG-implant’s contraceptive effect begins eight hours after insertion, and serum levels peak between days 4 and 20. The clearance of 3-KDSG is fast, and seven days after implant removal serum concentrations of 3-KDSG are decreased to <20 pg/ml. Ovulation resumes by six weeks after implant removal [74]. Serum levels slowly decrease over time, but as long as they remain above 90 pg/ml, this is sufficient to inhibit ovulation [75]. The primary mechanism of action of contraceptive implants is to thicken cervical mucus and to promote structural changes in the endometrium [76]. Although the ENG-implant inhibitis ovulation, one study observed some ovarian follicular activity and E2 levels were not suppressed although the mean serum levels of ENG were between 200 and 300pMol/l [76]. The mechanisms of action of the LNG-

16 implant are the same as those of the ENG-implant: anovulation, thickening of cervical mucus, and endometrial suppression [77].

Contraceptive efficacy The ENG-implant has a high contraceptive efficacy: its Pearl Index (PI) during initial studies was 0.0 (95% CI, 0.0 – 0.09) during 53,530 cycles (4,103 W-Y) [76]. Other authors reported the results of 11 clinical trials with 1,755 W-Ys of exposure, in which six pregnancies occurred at the end of three years of use, which resulted in a PI of 0.34 (95% CI 0.13-0.74). The authors reported that the pregnancies occurred within 14 days of implant removal [78]. One multicentre RCT comparing the two models of implants with 995 and 997 women allocated to ENG-implant and LNG-implant, respectively, reported three pregnancies in each group and the 3-year cumulative pregnancy rate was 0.4/100 W-Y (95% CI 0.1–1.4). A weight of ≥70 kg at admission was unrelated to pregnancy. Among LNG-implant users weighing ≥70 kg one pregnancy occurred (0.8/100 W-Y; 95% CI 1– 5.3) and others two other pregnancies were reported in the LNG-implant users among women with less than 70kg at the time of pregnancy the diagnosis. The pregnancies among the ENG-implant users also do not related to weight of the women [79]. The bioavailability of 3-KDSG remains close to 100% during three years of implant use [80]. Recent studies have confirmed that the ENG-implant remains highly effective even beyond three years [81]. One study of 223 ENG-implant users at the fourth year of use and of 102 women users at the fifth year use found mean serum ENG levels of 166.1 pg/ml (range 67.9 – 470.5 pg/ml) and 153.0 pg/ml (range 72.1–538.8 pg/ml), respectively [75]. The pregnancy rate was 0/100 W-Ys (1-sided 97.5% CI, 0 -

17 1.48) up to four years of use and 0/100 W-Ys (1-sided 97.5% CI, 0 to 2.65) at five years of use. Participants’ weight did not impact pregnancy rates [81]. Extended use of both the ENG and LNG implants was associated with high contraceptive effectiveness, and no pregnancies were reported in a study with 204 ENGimplant women and 330 LNG implant users [54,81].

Bleeding patterns and adverse effects The progestin released by implants induces endometrial changes, which change bleeding patterns. These may be abnormal and affect women’s quality of life. One paper reported the results of 11 trials with 946 ENG implant users followed for three years. Of these, 21.8% reported amenorrhoea, 33.3% reported infrequent bleeding, 6.1% reported frequent bleeding, and 16.9% reported prolonged bleeding [78]. The WHO trial that examined the two implant models reported discontinuation rates due to bleeding disturbances of 16.7/100 W-Ys (95% CI 14.4 – 19.3) for the ENG implant, and 12.5/100 W-Y (95% CI 10.5 – 14.9) for the LNG implant [79]. One trial conducted in Nigeria with 1,401 users of the LNG-implant reported that the main reason for early implant discontinuation was the wish to become pregnant (41.2%). Irregular bleeding was the third cause of discontinuation (11.3%) [82]. One of the side-effects observed among implant users is ovarian cyst formation (persistent ovarian follicles), which was seen at 12 months of use in 26.7% of ENGimplant users and 14.6% of LNG-implant users [83].

Postpartum contraception Immediate postpartum ENG-implant insertion is safe for both women and newborns [84] and is associated with low pregnancy rates during the first year of use

18 [85].

Furthermore, breastfeeding is not affected and no negative effects on the

newborns have been reported [86, 87].

Final comments The WHO estimates that although the global maternal mortality ratio (MMR) has decreased, the total number of maternal deaths in 2015 remained high: it was almost 303,000, which translates to 216 maternal deaths per 100,000 live births. In addition, low- and middle-income countries (as defined by the World Bank) account for 99% of global maternal deaths and their MMR (242/100,000) is 14 times higher than that of high-income countries (17/100,000) [88]. Many of the maternal deaths are associated with unplanned pregnancies. Furthermore, in developing regions, according to 2017 estimates, 214 million women of reproductive age have an unmet need for contraception. If all unmet need for modern contraception were satisfied the decline in UP could be approximately threequarters (from the current 89 million to 22 million per year) and the number of induced abortions could be reduced from 48 million to 12 million per year [89]. Increasing LARC access and encouraging its use has the potential to fill this gap and reduce the unmet need for contraception, as well as, the MMR and UP rate. One of the main characteristics of LARCs is that most of women are eligible for use after proper counselling. However, the high initial up-front cost can be a barrier depending on cost sharing schemes and varied levels of contraceptive coverage based on insurance plan. Other barriers to LARC use are remaining myths and misunderstandings about safety, as well as lack of trained Health Providers and facilities and poor counselling techniques [90]. It is important to reassure Health Providers about LARC use by nulligravidas and unmarried adolescents, to educate about the safety of IUDs, which are not

19 associated with PID/infertility, and to encourage immediate postpartum IUD and implant use [91]. Another common barrier to LARC use is that many Health Providers mistakenly believe that they can only be initiated during menses. Although this is recommended in order to guarantee that the woman is not pregnant, LARCs methods can be initiated at any time in the menstrual cycle, if the Health Provider can be reasonably sure the patient is not pregnant based on history and urine pregnancy testing. In addition to the high contraceptive effectiveness, LARCs provide many noncontraceptive benefits. The LNG IUS reduces menstrual bleeding, endometriosisassociated pain and dysmenorrhoea. The Cu-IUD reduces the risk of cervical and endometrial cancer and the ENG-implant improves endometriosis-related pain [58, 9294]. An added advantage of LARCs is that they are non-oestrogenic contraceptive methods, and as such they can be used safely by women with medical conditions like diabetes, hypertension, systemic lupus erythematosus, and endometrial hyperplasia, or by women with a history of solid organ transplantation, current or past of venous thromboembolism.

Finally, although the TCu380A IUD, the LNG 52mg IUS and the ENG-implant have thus far only been approved for use up to 10, 5 and 3 years, respectively, we now have convincing evidence to show that they can be used for up to 12-15 years, 7-10 years and 5 years, respectively [54, 96,97].

Summary The table shows a summary of LARC methods. Several LARC methods are currently approved in many countries. These include the 52mg LNG IUS, including the original device and at least three similar devices, as well as a 19.5mg and a 13.5mg

20 LNG IUS. They also include a two-rod LNG-releasing contraceptive implant (including a second device similar to the original one in some markets), and a one-rod ENGimplant. Finally, there are several models copper-bearing IUDs, with the TC380A IUD being the most popular and extensively distributed worldwide. Many studies have demonstrated that LARC methods are more effective to methods which require women’s periodic attention, such as pills, the patch, the vaginal ring or injectable methods. The effectiveness of LARC methods is comparable to that of female sterilization, and is independent of age, parity or BMI. These devices also have high continuation rates and many non-contraceptive benefits. In fact, adolescents and nulligravid women can safely use all LARC methods. The extremely low contraceptive failure of LARCs also means a reduced rate of ectopic pregnancies. However, LARCs are underutilized in many settings due to multiple factors. These include myths and misunderstandings on the part of potential users and providers, as well as lack of access to the devices. The high up-front cost, limited coverage by private insurances, and lack of availability in the public sector are barriers for millions of women worldwide. Abnormal uterine bleeding is the main cause of early discontinuation of LNG IUS and implants. Thorough counselling and anticipatory guidance are important and can help prevent early removals. Conflict of interest: LB and IM have received honoraria as members of advisory boards and have been invited speakers at scientific meetings for Bayer Healthcare Pharmaceuticals and Merck. None of the other authors have any conflicts of interest to declare.

21 Practice Points: •

Up today there are no effective therapies to avoid the discomfort or pain during intrauterine device placement.

•

LARC methods could be initiated at any time of the menstrual cycle if the Health Provider is sure that the woman is not pregnant.

•

The main reason for discontinuation among users of the LNG IUS and implants is abnormal bleeding. Counseling before placement and throughout the method use is the best strategy to enable the users to understand and accept these minor effects, and thus continue using the method.

•

Among the many non-contraceptive benefits associated with LARC use are decreased blood loss in cases of heavy menstrual bleeding, decreased endometriosis-associated pain and decreased endometrial proliferation among users of the 52mg LNG-IUS. Rates of cervical and endometrial cancer are lower among users of Cu-IUD.

Research Agenda:

•

More studies are needed to evaluate the real long-term cost of any unplanned pregnancy compared to the cost of LARC methods.

•

More studies are needed examining the insertion of LARC methods (intrauterine devices and implants) by cadres other than physicians.

•

More studies are needed to validate the extended use of the 52mg LNG-IUS up to seven years and the ENG-implant up to five years.

22 •

More studies are needed examining the benefits of LARC methods for women with medical conditions, including those with contraindications to oestrogen use.

References [1] Bahamondes L, Villaroel C, Guzmán NF, Oizerovich S, Velazquez-Ramirez N, Monteiro I. The use of long-acting reversible contraceptives in Latin America and the Caribbean: current landscape and recommendations. Hum Reprod Open, 2018;1:hox030.

[2] Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Nelson AL, et al., editors. Contraceptive Technology. 19. New York: Ardent Media; 2007. pp. 747–826.

* [3] Grimes D. Forgettable contraception. Contraception 2009;80:497-9. * [4] Winner B, Peipert JF, Zhao Q, et al. Effectiveness of long-acting reversible contraception. N Engl J Med 2012;366:1998–2007. [5] Mac Isaac L, Espey E. Intrauterine Contraception: The Pendulum Swings Back. Obstet Gynecol Clin North Am 2007;34:91-111. [6] Bahamondes L, Faundes A, Sobreira-Lima B, Lui-Filho JF, Pecci P, Matera S. TCu 380A IUD: a reversible permanent contraceptive method in women over 35 years of age. Contraception 2005;72:337-41. [7] Kulier R, Helmerhorst FM, O’Brien P, Usher-Patel M, d’Arcangues C. Copper containing, framed intra-uterine devices for contraception. Cochrane Database Syst Rev 2007;4:CD005347. [8] Trussell J. Contraceptive failure in the United States. Contraception 2011;83:397404.

23 [9] World Health Organization. Mechanism of action, safety and efficacy of intrauterine devices. World Health Organization (WHO); 1987 Technical Report Series 753. p. 91. Available from WHO, Geneva. [10] Alvarez F, Brache, E, Fernandez B, et al. New insights on the mode of action of intrauterine contraceptive devices in women. Fertil Steril 1988;49:768-73. [11] Tredway DR, Umezaki CU, Mishell DR Jr, Settlage DSF. Effect of intrauterine devices on sperm transport in the human being: preliminary report. Am J Obstet Gynecol 1975;123:734-5. [12] Aref IO, Kandi A, Tagi EL, Morad MR. Effects of non-medicated and copper IUDs on sperm migration. Contracept Del Syst 1983;4:203-6. [13] Sivin I. IUDs are contraceptives, not abortifacients: a comment on research and belief. Stud Fam Plann 1989;20:355-9. [14] Mishell DR. Intrauterine devices. Fertility Control Reviews 1992;3:3-12. [15] Moraes LG, Marchi NM, Pitoli AC, Hidalgo MM, Silveira C, Modesto W, et al. Assessment of the quality of cervical mucus among users of the levonorgestrel-releasing intrauterine system at different times of use. Eur J Contracept Reprod Health Care 2016;21:318-22. [16] Natavio MF, Taylor D, Lewis RA, Blumenthal P, Felix JC, Melamed A, et al. Temporal changes in cervical mucus after insertion of the levonorgestrel-releasing intrauterine system. Contraception 2013;87:426-31. [17] Meirik O, Rowe PJ, Peregoudov A, Piaggio G, Petzold M; IUD Research Group at the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction. The frameless copper IUD (GyneFix) and the TCu380A IUD: results of an 8-year multicenter randomized comparative trial. Contraception 2009;80:133-41.

24 [18] UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, IUD Research Group. A randomized multicentre trial of the Multiload 375 and TCu 380A IUDs in parous women: three-year results. Contraception 1994;49:543–9. * [19] Heinemann K, Reed S, Moehner S, Minh TD.

Comparative contraceptive

effectiveness of levonorgestrel-releasing and copper intrauterine devices: the European Active Surveillance Study for Intrauterine Devices. Contraception 2015;91:280-3. [20] Sivin I. Dose- and age-dependent ectopic pregnancy risks with intrauterine contraception. Obstet Gynecol 1991;78:291-8. [21] Mansour D, Inki P, Gemzell-Danielsson K. Efficacy of contraceptive methods: a review of the literature. Eur J Contracept Reprod Health Care 2010;15:4-16. [22] Sivin I, el Mahgoub S, McCarthy T, Mishell Jr DR, Shoupe D, Alvarez F, et al. Long-term contraception with the levonorgestrel 20 mcg/day (LNg 20) and the copper T 380Ag intrauterine devices: a five-year randomized study. Contraception 1990;42:36178. [23] Ganacharya S, Bhattoa HP, Batár I. Ectopic pregnancy among non-medicated and copper-containing intrauterine device users: a 10-year follow-up. Eur J Obstet Gynecol Reprod Biol 2003;111:78-82. [24] Bahamondes L, Makuch MY, Monteiro I, Marin V, Lynen R. Knowledge and attitudes of Latin American obstetricians and gynecologists regarding intrauterine contraceptives. Int J Womens Health 2015;7:717-22. * [25] World Health Organization. Medical eligibility criteria for contraceptive use. 5th ed. Geneva: World Health Organization; 2015.

25 [26] Bahamondes MV, Hidalgo MM, Bahamondes L, Monteiro I. Ease of insertion and clinical performance of the levonorgestrel-releasing intrauterine system in nulligravidas. Contraception 2011;84:e11-6. [27] Morgan IA, Zapata LB, Curtis KM, Whiteman MK. Health care provider attitudes about the safety of "Quick Start" initiation of long-acting reversible contraception for adolescents. J Pediatr Adolesc Gynecol 2019; in press. [28] Finer L, Zolna MR. Declines in unintended pregnancy in the United States, 20082011. N Engl J Med 2016:374:843-52. [29] Jackson E, Glasier A. Return of ovulation and menses in postpartum nonlactating women: a systematic review. Obstet Gynecol 2011;117:657–62. [30] World Health Organization. Report of a WHO technical consultation on birth spacing. Geneva: World Health Organization; 2005. [31] Kapp N, Curtis KM. Intrauterine device insertion during the postpartum period: a systematic review. Contraception 2009;80:327–36. [32] Heller R, Cameron S, Briggs R, Forson N, Glasier A. Postpartum contraception: a missed

opportunity

to

prevent

unintended pregnancy and

short

inter-

pregnancy intervals. J Fam Plann Reprod Health Care 2016;42:93-8. [33]

Whitaker

AK, Chen

BA.

Society

of

Family

Planning

Guidelines:

Postplacental insertion of intrauterine devices. Contraception 2018;97:2-13. [34] Curtis KM, Tepper NK, Jatlaoui TC, Berry-Bibee E, Horton LG, Zapata LB, et al. U.S. medical eligibility criteria for contraceptive use. MMWR Recomm Rep 2016;65:1–103. [35] American College of Obstetricians and Gynecologists. Immediate postpartum longacting reversible contraception. Committee Opinion No. 670. Obstet Gynecol 2016;128:e32–7.

26 [36] Jatlaoui TC, Whiteman MK, Jeng G, Tepper NK, Berry-Bibee E, Jamieson DJ, et al. Intrauterine device expulsion after postpartum placement: a systematic review and meta-analysis. Obstet Gynecol 2018;132:895–905. [37] Brahmi D, Steenland MxW, Renner R-M, Gaffield ME, Curtis KM. Pregnancy outcomes with an IUD in situ: a systematic review. Contraception 2012;85:131–9. [38] Kirkinen P, Simojoki M, Kivela A, Jouppila P. Ultrasound-controlled removal of a dislocated intrauterine device in the first trimester of pregnancy: a report of 26 cases. Ultrasound Obstet Gynecol 1992;2:345–8. [39] Schiesser M, Lapaire O, Tercanli S, Holzgreve W. Lost intrauterine devices during pregnancy: maternal and fetal outcome after ultrasound guided extraction. An analysis of 82 cases. Ultrasound Obstet Gynecol 2004;23:486–9. [40] Nilsson CG, Luukkainen T, Diaz J, et al. Intrauterine contraception with levonorgestrel: a comparative randomised clinical performance study. Lancet 1981;1:577–80. [41] Sivin I, Tatum HJ. Four years of experience with the TCu 380A intrauterine contraceptive device. Fertil Steril 1981;36:159-63. [42] Sivin I, Diaz J, Alvarez F, Brache V, Diaz S, Pavez M, et al. Four-year experience in a randomized study of the Gyne T 380 Slimline and the Standard Gyne T 380 intrauterine copper devices. Contraception 1993;47:37-42. [43] Phillips SJ, Hofler LG, Modest AM, Harvey LFB, Wu LH, Hacker MR. Continuation of copper and levonorgestrel intrauterine devices: a retrospective cohort study. Am J Obstet Gynecol 2017;217:57.e1-57.e6. [44] Rivera R, Chen-Mok M, McMullen S. Analysis of client characteristics that may affect early discontinuation of the TCu-380A IUD. Contraception 1999;60:155-60.

27 [45] Luukkainen T, Allonen H, Nielsen NC, et al. Five years’ experience of intrauterine contraception with the Nova-T and the Copper T 200. Am J Obstet Gynecol 1983;147:885–92. [46] Madden T, McNicholas C, Zhao Q, et al. Association of age and parity with intrauterine device expulsion. Obstet Gynecol 2014;124:718-26. [47] Diedrich JT, Klein DA, Peipert JF. Long-acting reversible contraception in adolescents: a systematic review and meta-analysis. Am J Obstet Gynecol 2017;216:364.e1-364.e12. [48] Steenland MV, Zapata LB, Brahmi D, Marchbanks PA, Curtis KM. The effect of follow-up visits or contacts after contraceptive initiation on method continuation and correct use. Contraception. 2013;87:625–30. [49] Bahamondes L, Monteiro I, Fernandes A, Gaffield ME. Follow-up visits to check strings after intrauterine contraceptive placement cannot predict or prevent future expulsion. Eur J Contracept Reprod Health Care 2019;24:97-101. [50] Grimes DA. Intrauterine device and upper-genital-tract infection. Lancet 2000;356: 1013–9. [51] Hubacher D, Lara-Ricalde R, Taylor DJ, Guerra-Infante F, Guzman-Rodriguez R. Use of copper intrauterine devices and the risk of tubal infertility among nulligravid women. N Engl J Med 2001;345:561–7. [52] Barnett C, Moehner S, Do Minh T, Heinemann K. Perforation risk and intra-uterine devices: results of the EURAS-IUD 5-year extension study. Eur J Contracept Reprod Health Care 2017;22:424-8. * [53] Luukkainen T, Pakarinen P, Toivonen J. Progestin-releasing intrauterine systems. Semin Reprod Med 2001;19:355-63.

28 * [54] Ali M, Bahamondes L, Bent Landoulsi S. Extended Effectiveness of the Etonogestrel-Releasing Contraceptive Implant and the 20 µg Levonorgestrel-Releasing Intrauterine System for 2 Years Beyond U.S. Food and Drug Administration Product Labeling. Glob Health Sci Pract. 2017;5:534–9. [55] Hidalgo MM, Hidalgo-Regina C, Bahamondes MV, Monteiro I, Petta CA, Bahamondes L. Serum levonorgestrel levels and endometrial thickness during extended use of the levonorgestrel-releasing intrauterine system. Contraception. 2009;80:84-9. [56] Seeber B, Ziehr SC, Gschlieβer A, et al. Quantitative levonorgestrel plasma level measurements in patients with regular and prolonged use of the levonorgestrel-releasing intrauterine system. Contraception 2012;86:345-9. [57] Petta CA, Ferriani RA, Abrao MS, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod 2005;20:1993-8. [58] Bahamondes L, Valeria Bahamondes M, Shulman LP. Non-contraceptive benefits of hormonal and intrauterine reversible contraceptive methods. Hum Reprod Update 2015;21:640-51. [59] Bayer Ltd., The Atrium, Blackthorn Road, Sandyford, Dublin 18. Differentiation of Kyleena, Jaydess and Mirena intrauterine delivery systems (Levonorgestrel). Available at: https://www.hpra.ie/img/uploaded/swedocuments/Kyleena_HCP_Differentiation%20of %20Kyleena%2C%20Jaydess%20and%20Mirena_090117-2184258-10022017094820636223169107858750.pdf. Accessed September 11, 2019.

29 [60] Wildemeersch D, Andrade A, Goldstuck N. Femilis(®) 60 LevonorgestrelReleasing Intrauterine System-A Review of 10 Years of Clinical Experience. Clin MedInsights Reprod Health 2016;10:19-27. * [61] [Apter D, Gemzell-Danielsson K, Hauck B, et al. Pharmacokinetics of two lowdose levonorgestrel-releasing intrauterine systems and effects on ovulation rate and cervical function: pooled analyses of phase II and III studies. Fertil Steril 2014;101:1656-62.e1-4. [62] Goldstuck ND. Clarification of the role of the Jaydess (Skyla) LNG- IUS 13.5mg and Kyleena LNG-IUS 19.5mg as intrauterine contraceptive systems. Expert Rev Med Devices 2017;14:593-9. [63] Goldthwaite LM, Creinin MD. Comparing bleeding patterns for the levonorgestrel 52 mg, 19.5 mg, and 13.5 mg intrauterine systems. Contraception 2019;100:128-31. [64] Gemzell-Danielsson K, Schellschmidt I, Apter D. A randomized, phase II study describing the efficacy, bleeding profile, and safety of two low-dose levonorgestrelreleasing intrauterine contraceptive systems and Mirena. Fertil Steril 2012;97:616–22. [65] Gemzell-Danielsson K, Apter D, Dermout S, et al. Evaluation of a new, low-dose levonorgestrel intrauterine contraceptive system over 5 years of use. Eur J Obstet Gynecol Reprod Biol 2017;210:22–8. [66] Hidalgo M, Bahamondes L, Perrotti M, Diaz J, Dantas-Monteiro C, Petta C. Bleeding patterns and clinical performance of the levonorgestrel-releasing intrauterine system (Mirena) up to two years. Contraception 2002;65:129-32. [67] ACOG Committee Opinion No. 735: Adolescents and Long-Acting Reversible Contraception: Implants and Intrauterine Devices. Obstet Gynecol 2018;131:e130-e139; [68] Daniels K, Abma JC. Centers for Disease Control and Prevention. Current Contraceptive Status Among Women Aged 15–49: United States, 2015–2017. Available

30 at: https://www.cdc.gov/nchs/data/databriefs/db327-h.pdf Accessed September 11, 2019. [69] Itriyeva K. Use of Long-Acting Reversible Contraception (LARC) and the DepoProvera Shot in Adolescents. Curr Probl Pediatr Adolesc Health Care 2018;48:321-32. [70] Backman T, Rauramo I, Huhtala S, Koskenvuo M. Pregnancy during the use of levonorgestrel intrauterine system. Am J Obstet Gynecol 2004;190:50–4. [71] Hopkins MR, Agudelo-Suarez P, El-Nashar SA, Creedon DJ, Rose CH, Famuyide AO. Term pregnancy with intraperitoneal levonorgestrel intrauterine system: a case report and review of the literature. Contraception 2009;79:323–7. * [72] Le J, Tsourounis C. Implanon: a critical review. Ann Pharmacother 2001;35:32936. [73] Bergink EW, Hamburger AD, de Jager E, van der Vies J.: Binding of a contraceptive progestogen Org 2969 and its metabolites to receptor proteins and human sex hormone binding globulin. J Steroid Biochem 1981;14:175-83. [74] Makarainen L, van Veek A, Tuomivaara L, Asplund B, Coelingh-Ben- nink H. Ovarian function during the use of a single contraceptive implant: Implanon compared with Norplant. Fertil Steril 1998;69:714-21. [75] Diaz S, Pavez M, Moo-Young AJ, Bardin CW, Croxatto HB. Clinical trial with 3keto-desogestrel subdermal implants. Contraception. 1991; 44(4): 393–408. [76] Croxatto HB, Makarainen L. The pharmacodynamics and efficacy of Implanon. An overview of the data. Contraception 1998;58(6 Suppl):91S–7S. [77] Brache V, Faundes A, Johansson E, Alvarez F. Anovulation, inadequate luteal phase and poor sperm penetration in cervical mucus during prolonged use of Norplant implants. Contraception 1985;31:261-73.

31 [78] Darney P, Patel A, Rosen K, Shapiro LS, Kaunitz AM. Safety and efficacy of a single-rod etonogestrel implant (Implanon): results from 11 international clinical trials. Fertil Steril 2009;91:1646-53. [79] Bahamondes L, Brache V, Meirik O, Ali M, Habib N, Landoulsi S. A 3-year multicentre randomized controlled trial of etonogestrel- and levonorgestrel-releasing contraceptive implants, with non-randomized matched copper-intrauterine device controls. Hum Reprod 2015;30:2527-38. [80] Huber J. Pharmacokinetics of Implanon. Contraception 1998;58(6 sup- pl):85S90S) * [81] McNicholas C, Maddipati R, Zhao Q, Swor E, Peipert,JF. Use of the etonogestrel implant and levonorgestrel intrauterine device beyond the U.S. Food and Drug Administration-approved duration. Obstet Gynecol 2015;125:599-604. [82]

Pam VC, Mutihir JT, Nyango DD, Shambe I, Egbodo CO, Karshima JÁ.

Sociodemographic profiles and use-dynamics of Jadelle (levonorgestrel) implants in Jos, Nigeria. Niger Med J 2016;57:314-9. [83] Hidalgo MM, Lisondo C, Juliato CT, Espejo-Arce X, Monteiro I, Bahamondes L. Ovarian cysts in users of Implanon and Jadelle subdermal contraceptive implants. Contraception 2006;73:532-6. [84] Phillips SH, Tepper NK, Kapp N, Nanda K Temmerman M, Curtis KM. Progestogen-only contraceptive use among breastfeeding women: a systematic review. Contraception 2016;94:226-52. [85] Brunson MR, Klein DA, Olsen CH, Weir LF, Roberts TA. Postpartum contraception: initiation and effectiveness in a large universal healthcare system. Am J Obstet Gynecol 2017;217:55.e1-55.e9.

32 [86] Taneepanichskul S, Reinprayoon D, Thaithumyanon P, Praisuwanna P, Tosukhowong P, Dieben T. Effects of the etonogestrel-releasing implant Implanon and a nonmedicated intrauterine device on the growth of breast-fed infants. Contraception 2006;73:368–71. [87] Bahamondes L, Bahamondes MV, Modesto W, et al. Effect of hormonal contraceptives during breastfeeding on infant's milk ingestion and growth. Fertil Steril 2013;100:445–50. [88] Tracking Progress towards Universal Coverage for Reproductive, Newborn and Child Health: The 2017 Report. Washington, DC: United Nations Children’s Fund (UNICEF) and the World Health Organization (WHO), 2017.

Available at:

http://countdown2030.org/pdf/Countdown-2030-complete-with-profiles.pdf.

Accessed

September 3 2019. [89] Darroch JE, Sully E. Adding It Up: Investing in Contraception and Maternal and Newborn Health, 2017. New York. Guttmacher Institute, 2017. [90] Gavin L, Frederiksen B, Robbins C, Pazol K, Moskosky S. New clinical performance measures for contraceptive care. Contraception 2017;96:149-57. [91] Zhu H, Lei H, Huang W, Fu J, Wang Q, Shen L, et al. Fertility in older women following removal of long-term intrauterine devices in the wake of a natural disaster. Contraception 2013;87:416-20. * [92] Castellsagué X, Díaz M, Vaccarella S, et al. Intrauterine device use, cervical infection with human papillomavirus, and risk of cervical cancer: a pooled analysis of 26 epidemiological studies. Lancet Oncol 2011;12:1023-31. [93] Carvalho N, Margatho D, Cursino K, Benetti-Pinto CL, Bahamondes L. Control of endometriosis-associated pain with etonogestrel-releasing contraceptive implant and 52-

33 mg levonorgestrel-releasing intrauterine system: randomized clinical trial. Fertil Steril 2018;110:1129-36. [95] Wu JP, Moniz MH, Ursu AN. Long-acting reversible contraception-Highly efficacious, safe, and underutilized. JAMA 2018;320:397-8. [96] Bahamondes L, Fernandes A, Bahamondes MV, Juliato CT, Ali M, Monteiro I. Pregnancy outcomes associated with extended use of the 52-mg 20 µg/day levonorgestrel-releasing intrauterine system beyond 60 months: A chart review of 776 women in Brazil. Contraception 2018;97:205-9. [97] Ali M, Akin A, Bahamondes L, Brache V, Habib N, Landoulsi S, et al. Extended use up to 5 years of the etonogestrel-releasing subdermal contraceptive implant: comparison to levonorgestrel-releasing subdermal implant. Hum Reprod 2016;31:24918.

Table. Summary of the long-acting reversible contraceptive methods (LARC) available worldwide. Contraceptive Method

Approved label years of use

Main Noncharacteristics contraceptive benefits

TCu380A IUD

10

LNG 52mg IUS (Mirena, Liletta, Levosert, Avibella)

5

LNG 19.5 mg IUS (Kyleena)

5

LNG 13.5 mg IUS (Jaydess, Skyla)

3

LNG implant (Jadelle, SinoImplant)

5

No hormonal, pain and bleeding disturbances are the main reasons for discontinuation Highly effective as emergency contraception Hormonal, oestrogen free, bleeding disturbances and hormonal signs are the main reasons for discontinuation Smaller device, hormonal, oestrogen free, bleeding disturbances and hormonal signs are the main reasons for discontinuation Smaller device, hormonal, oestrogen free, bleeding disturbances and hormonal signs are the main reasons for discontinuation Hormonal, oestrogen free, bleeding

Reduction of cervical and endometrial cancer

Reduction of endometriosisassociated pain and dysmenorrhea, ovarian and endometrial cancer (Only for Mirena)

Scientific publications on extended use (years) 12-15

7 -9 years

ENG implant (Implanon NXT)

3

disturbances and hormonal signs are the main reasons for discontinuation Hormonal, bleeding disturbances and hormonal signs are the main reasons for discontinuation

Reduction of endometriosisassociated pain, dysmenorrhea and adenomyosis

5 years

Highlights: •

LARC methods are associated with lower contraceptive failure rates compared to other methods.

•

Contraceptive efficacy of LARCs is independent of user age, parity and body mass index.

•

Myths and misconceptions about LARCs have halted their expansion as a first line contraception.

•

LARC methods can be use by nulligravidas women and adolescent girls.

•

Use of LARC methods is associated to many non-contraceptive benefits.

Campinas, 4 DEcember, 2019 Beverly Burns Editorial Office Best Practice & Research Clinical Obstetrics & Gynecology Dear Beverly We introduce all the changes required by the reviewers and they are highlighted in red in the new text Yours sincerely Dr Luis Bahamondes 1.

Document Page 9/ pdf page 16 Line 22

From They can also increases To This can also increase Answer: Change as requested 2.

Document Page 11/ pdf page 18 Line 36

Use The prevalence of IUC use was low Answer: Change as requested

3.

Document Page 17/ pdf page 24

Line 7 *

No pregnancies WERE reported

Answer: Change as requested Line 17 *

Endometrial changes, which CHANGE bleeding patterns

Answer: Change as requested

Line 39 *

Was THE wish

Answer: Change as requested 4.

Document page 20/ pdf page 27, Line 39

Though counseling and anticipatory guidance ARE…. Answer: Change as requested

5.

Document Page 21/ pdf page 28

Line 6 to 8 Second Practice point From *

LARC methods could initiate at any time of the menstrual cycle if the professional

are sure that the woman is not pregnant. To *

LARC methods could BE initiated at any time of the menstrual cycle if the HEALTH

PROVIDER is sure that the woman is not pregnant. Answer: Change as requested

Line 50 to 52 *

I suggest to remove "professional"

Answer: Change as requested Line 57 *

To VALIDATE or EVALUATE the extended use

Answer: Change as requested

6.

DOCUMENT Page 21/ pdf page 28 Line 15 to 17.

From *

Counselling before placement and throughout method use is the best strategy to

minimize this kind of adverse effect.

To *

Counseling before placement and throughout the method use is the best strategy

to enable the users to understand and accept these minor effects, and thus continue using the method-.... Answer: Change as requested 7.

Pdf Page 48

PearL index - in the explanation to the answer to Q 3 Answer: Change as requested 8.

Pdf document Page 50

In Highlights: Can BE used by nulligravidas and adolescent females Answer: Change as requested 9.

PDF PAGE 41 AND 51

*

Please modify the changes here proposed in the earlier pages on research

Answer: Change as requested

Campinas, 4 December, 2019 Beverly Burns Editorial Office Best Practice & Research Clinical Obstetrics & Gynecology Dear Beverly Please find enclosed our revised version of the manuscript: Ms. Ref. No.: YBEOG-D-19-903 Title: Long-acting reversible contraceptive (LARCs) methods Best Practice & Research Clinical Obstetrics & Gynecology which we like to re-submit to the journal. We introduce all the changes required by the reviewers and they are highlighted in red in the new text Yours sincerely Dr Luis Bahamondes Comments on the Paper on LARCs, 1.

It is a well written paper, with a good balance of research evidence, clinical

practice points and strategies for increased use. 2.

There are some minor typographical changes to be made:

a.

Page 3, line 7. Correct Ups to UPS

Answer: We corrected b.

Page 4, line 23. I suggest changing "behavioural" to "behavior related".

Answer: We corrected c.

Page 5. First paragraph on the page. I would request that we put a line that many

of the recommended strategies stated are off label use, and are not yet included in many guideline recommendations from international or national bodies. Answer: We included as requested d.

Page 5. Second paragraph. Since the journal is mostly a clinical practice journal, it

may help to add a few lines regarding the characteristics and management of the symptoms of pain and of bleeding. Answer: We included as requested in page 11. e.

Page 8. Section on Immediate postpartum IUC use. Line 39. Correct the line "This

practice I justified,,," to " This practice is justified…"

Answer: We corrected f.

Page 11. Line 35. HC P refers to Health care professionals. For the purposes of the

journal ^, we may want to use the term "Health Providers" instead. Answer: We corrected g.

Page 16. Line 1. Correct Pear to Pearl

Answer: We corrected h.

Page 21. Line 21. LARC methods could BE initiated.

Answer: We corrected i.

Page 21. Line 33. I suggest we change the line "best strategy< to minimize this

kind of adverse effect…" to "best strategy enable the users to understand and accept these minor effects, and thus continue using the method-…. Answer: I was unable to find out this text j.

Page 34. I am not sure if he journal allows brand names of commodities to be

listed.

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