CLINICAL OBSTETRICS & GYNAECOLOGY

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

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

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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
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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 copper￾bearing 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.
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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 Cu￾IUDs. 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
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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
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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 0.1-
1.0 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
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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
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(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
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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].
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One study conducted by the WHO [17] compared the frameless Cu￾IUD (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].
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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 (W￾Y) [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
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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
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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,
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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 etonogestrel￾releasing 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-
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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 -
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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 ENG￾implant 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 ENG￾implant 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
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[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 three￾quarters (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 non￾contraceptive benefits. The LNG IUS reduces menstrual bleeding, endometriosis￾associated pain and dysmenorrhoea. The Cu-IUD reduces the risk of cervical and
endometrial cancer and the ENG-implant improves endometriosis-related pain [58, 92-
94]. 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 ENG￾implant. 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.
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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
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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