Abstract

Long-acting reversible contraception—intrauterine devices and contraceptive implants—offers

the highest protection against unintended pregnancies. In addition, the use of reversible hormonal
contraception has added health benefits for women in both the short and the long term. This
review will give an overview of the benefits of reversible contraception as well as an evidence-
based recommendation on how it should be used to benefit women the most.

Keywords: Contraception, unintended pregnancy, abortion, LARC

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Introduction
In 2012, approximately 213 million pregnancies occurred worldwide 1. An unintended pregnancy
is defined as a pregnancy that is unwanted or mistimed. In 2012, approximately 40% of all
pregnancies were unintended, with 38% ending in live birth, 50% in abortion, and 13% in
miscarriage 1. New data published in 2018 show that unintended pregnancies declined unevenly
in the world, reflecting large differences in unmet need for contraception. In 2010–2014, 56% of
unintended pregnancies ended in abortion, indicating that fewer women chose birth when
confronted with an unintended pregnancy 2. Unintended and intended pregnancies alike may also
result in the same proportion of miscarriage or ectopic pregnancy, which may result in
subsequent subfertility or infertility.

It has been shown that long-acting reversible contraception (LARC)—intrauterine devices

(IUDs) and contraceptive implants—offers the highest protection against unintended
pregnancies. However, LARCs are rarely recommended for young women with high fertility.
Short-acting reversible contraception (SARC) such as contraceptive pills, patches, rings, and
injections are user dependent. Thus, the risk of getting pregnant because of inconsistent use is
higher than for LARC.

In addition to protection against unintended pregnancy, the use of reversible hormonal

contraception has added health benefits for women in both the short and the long term. The
short-term added health benefits include a reduction of menstrual blood flow and protection
against anemia, a reduction in dysmenorrhea and possible protection from symptoms of
endometriosis, and a positive effect on mood in the premenstrual period. In the long term, all
reversible contraception can be protective against some forms of cancer 3.

In recent years, new ways of using reversible contraception have extended benefits for women
and improved acceptability. This review will give an overview of the benefits of reversible
contraception as well as an evidence-based recommendation on how it should be used to benefit
women the most.

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Protection against unintended pregnancy

In many parts of the world, unintended pregnancies arise from a lack of access to safe
contraceptive methods. However, in parts of the world where efficient contraception is easily
accessible, underutilization or user error is a common reason for contraceptive failure resulting in
unintended pregnancy. Thus, reasons for unmet need of contraception vary in different settings.
Most evidence on contraceptive use comes from women living in union (defined as traditional or
legal marriage). Contraceptive use among young women not living in union in low-resource
settings is less well known. Use of modern contraception was practiced globally by 57% of
women living in union in 2015 4. Therefore, presumably a large proportion of women globally
have an unmet need for modern contraceptive methods.

LARC, such as subdermal implants and IUDs, results in significantly lower rates of unintended
pregnancies owing to less user error compared to other methods, especially among young users
who have lower user adherence 5, 6. LARCs also have higher satisfaction compared to SARC and
higher continuation rates at 12 months 7. After an induced abortion, the use of LARC has been
shown to reduce subsequent induced abortions due to unintended pregnancy 8– 10.

Although most women spend the majority of their fertile period trying to avoid pregnancy, the
worldwide use of IUDs is estimated to be 14% 4, and the use of implants is much lower 4. In low-
resource settings, the use of LARC is limited by access to health care professionals (HCPs) for
placement and removal 4.

Among barriers to using IUDs in high-resource settings, fear of pain at insertion is commonly
stated 11, 12. However, studies performed with an inserter 4.8 mm in diameter could not confirm
that nulliparous women experience severe pain during insertion 13, 14. Recent studies have
included insertion tube diameters of 3.8 and 4.8 mm. These studies confirm that less than 7% of
women experience severe pain with the 4.8 mm insertion tube but that significantly fewer
experience such pain with a 3.8 mm insertion tube 14. Thus, refraining from insertion of IUD in
nulliparous women due to the patient’s fear of experiencing severe pain is not in line with current
evidence, although there is still an ongoing debate.

Ectopic pregnancy and the use of contraception

The focus on outcomes of unintended pregnancy tends to be on those that women can choose
actively, i.e. abortion or birth. However, approximately 2% of all pregnancies are ectopic
pregnancies 15, 16, which is the leading cause of maternal mortality in the first trimester and
accounts for approximately 9% of maternal mortalities in the US 16– 18. LARC, such as IUDs, are
user independent with a low risk of unintended pregnancy at 0.1–0.2% of women per user year 6,
19, 20
. However, if pregnancy occurs, approximately 25–50% of these pregnancies are ectopic 18.
Thus, LARC use reduces the risk of ectopic pregnancy compared to SARC use.

Risk factors for ectopic pregnancy include previous history of ectopic pregnancy, pelvic surgery,
pelvic infections (pelvic inflammatory disease [PID]) such as sexually transmitted infections
including chlamydia trachomatis, assisted reproductive technology, smoking, and use of
intrauterine contraception 17, 21. These are generally not considered as contraindications for use of
intrauterine contraception owing to the high contraceptive efficacy of the current devices and the
failure rate of SARC due to inconsistent use.
Methods for reducing risks of unintended pregnancy due to inconsistent use of
pills, patches, and rings

The most common combination contraceptive pills and the available patch and ring all come
with a hormone-free period of 7 days, during which women typically have a withdrawal bleed.
Follicle growth starts on day 1 in the normal menstrual cycle. That follicle growth and ovarian
suppression would therefore be affected by the length of the hormone-free period would seem
logical, i.e. the longer time span without suppression, the larger the follicle grows and the closer
the woman comes to ovulation. The benefit of a shorter hormone-free period has been previously
suggested 22. Research shows that escape ovulation may occur with a 7-day hormone-free period
23
. Although these escape ovulations may be due to inconsistent use of the method, they may also
be due to a short menstrual cycle where ovulation may occur as early as 10 days into the
menstrual cycle. In this study, the formulation with a 4-day hormone-free period produced a
higher level of ovarian suppression. The higher level of ovarian suppression with a 4-day
hormone-free period compared to a 7-day hormone-free period was confirmed in another trial
where the size of the ovarian follicle was measured 24. Thus, recommending a maximum 4-day
hormone-free period may be beneficial when counseling women who wish to avoid pregnancy.
The effectiveness of pills in typical use has been shown to be higher with a hormone-free period
of 4 days compared with 7 days 25.

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Short-term added health benefits with reversible

contraception
Reduction in menstrual bleeding

Although choice of method may influence bleeding patterns and menstrual pain, recent research
also focuses on how different methods can be used for the best effects on health and well-being.
Using contraceptive pills/rings or patches for an extended but defined period of time may be
called extended or long-cycle use. Using the same methods for longer periods of time until
bleeding occurs may be called flexible continuous use. Recently, a Cochrane review evaluated
continuous or extended use versus routine cyclic use of combined hormonal contraceptives for
contraception 26. The review was based on 12 randomized controlled trials and concluded that
there was no difference in compliance between regular 28-day cycles or extended or continuous
use nor was there any difference in discontinuation or discontinuation due to experienced
bleeding problems. The extended or continuous regimens fared better in terms of headaches,
genital irritation, tiredness, bloating, and dysmenorrhea.

A recent study compared three groups of women. One group adhered to a 24/4 cycle, a second
group took a 4-day pill-free break when experiencing a 3-day bleeding episode, and a third group
could choose when to have a 4-day pill-free break. It was concluded that women in the second
group had the fewest bleeding days during 1 year 27. There is evidence that the combined
hormonal ring may also be used in continuous or extended regimens similar to those of pills 28. It
is therefore possible that advising women on how to use their combined hormonal contraception
may contribute more to user satisfaction than which combined hormonal pill is prescribed. There
are no prospective studies comparing continuous or extended cycle use with a 24/4 regimen in
terms of contraceptive effectiveness.

Evidence suggests that a newer formulation of combined hormonal contraceptive pills with
estradiol valerate reduces menstrual blood flow in women with heavy menstrual bleeding by as
much as 90% when taken according to the manufacturer’s instruction 29 compared to a reduction
of 43% with older formulations taken with a 7-day hormone-free period 30. Taking pills with
estradiol and nomegestrol acetate reduces the number of cycles without any bleeding when
compared to pills containing ethinyl estradiol and drospirenone if the pills are taken with a 24/4
or 21/7 regimen according to the manufacturer’s instructions 31. No comparative trials of
bleeding patterns with extended or continuous regimens for pills containing estradiol/estradiol
valerate or ethinyl estradiol have been published.

The most-effective method for reducing menstrual bleeding is the 52 mg levonorgestrel (LNG)-
releasing intrauterine system (LNG-IUS) 32. In addition to providing women with a reduction in
menstrual bleeding, the LNG-IUS provides women with a highly effective LARC. Until a few
years ago, the only available LNG was the 52 mg LNG-IUS approved for 4 or 5 years of use
depending on the brand. New evidence suggests that one of the 52 mg LNG-IUS may be used
beyond 5 years 33. There are now two additional LNG-IUS with hormone capsules containing
13.5 mg and 19.5 mg LNG, respectively. The 13.5 mg LNG-IUS is approved for 3 years of use,
whereas the 19.5 mg LNG-IUS is approved for 5 years of use. All LNG-IUS reduce menstrual
bleeding. The 52 mg LNG-IUS is approved for the treatment of heavy menstrual bleeding and
has been shown to reduce bleeding by up to 92% 32, 34. No such trials have been performed for the
13.5 mg or 19.5 mg LNG-IUS. In a randomized controlled trial comparing the three LNG-IUS,
there were 23.6%, 18.9%, and 12.7% cycles without any bleeding in the 52 mg, 19.5 mg, and
13.5 mg LNG-IUS, respectively, at the end of the trial, which lasted for 3 years 14. This makes a
dose-response relationship in bleeding pattern likely. No comparative trials have been published
for the treatment of heavy menstrual bleeding with extended- or continuous-use regimens of
combined hormonal contraception and the LNG-IUS.

Premenstrual mood

It has been estimated that as many as 75% of women experience a negative effect on mood in the
premenstrual phase and that approximately 3–5% of women have premenstrual dysphoric
disorder with severe negative mood changes and experience social impairment because of this 35.
The effect of hormonal contraception on premenstrual dysphoric syndrome/disorder has been
investigated in reviews 36 and systematic reviews 37. These studies show that combined oral
contraception improves premenstrual symptoms. A recent double blind randomized placebo-
controlled trial of the effect on mood of a combined oral contraceptive containing 1.5 mg
estradiol and nomegestrol acetate showed a significant improvement of mood in the premenstrual
phase in the intervention group 38. However, this was not a trial on premenstrual dysphoric
syndrome/disorder but with normal, healthy women. Healthy women with mild premenstrual
symptoms may thus be advised that combined hormonal contraception may have a beneficial
effect on mood during the premenstrual phase. In this trial, there was a non-significant worsening
of mood in the early intermenstrual phase. However, the nocebo effect was pronounced, with as
many as 17% of women in the placebo group and 24% of women in the intervention group
indicating a worsening of mood during and after bleeding. Thus, a majority of women who
indicate a worsening of mood may in fact experience a nocebo effect.

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Long-term added health benefits

Effects on cancer

The effect of combined hormonal contraceptive pills on cancer has been studied in retrospective,
prospective, and epidemiological studies. Results are partly consistent and partly contradictory.
In 2017, the newest prospective data were published from the Royal College of General
Practitioners’ oral contraception study, which recruited women in Great Britain in 1968 and 1969
39
. It concluded that ever use of combined oral contraceptives was associated with a reduced risk
of colorectal cancer (incidence rate ratio 0.81; 99% confidence interval [CI] 0.66–0.99),
endometrial cancer (incidence rate ratio 0.66; 99% CI 0.48–0.89), and ovarian cancer (incidence
rate ratio 0.67; 99% CI 0.50–0.89). In addition, a reduction in lymphatic and hematopoietic
cancer (incidence rate ratio 0.74; 99% CI 0.58–0.94) was seen. Several studies have shown an
increase in breast cancer during current use of combined hormonal contraception, which was
confirmed in a meta-analysis of these studies 40. However, this risk could not be confirmed in the
Oxford Family Planning Association oral contraceptive study 41. However, those studies that
showed an increased risk also showed that this increased risk does not persist 5–15 years after
stopping combined hormonal contraception, whereas the reduction in risks of ovarian,
endometrial, and colon cancer persisted 39, 42, 43. In addition, no new increased cancer risks
appeared later in life in any of the studies. In the large prospective Nurses’ Health study with
results published in 2014, it was concluded that groups with use or non-use of combined oral
contraception did not differ in all-cause mortality 42. In all large prospective studies, women were
married and cohabitating. Women in the Nurses’ Health study were 30–55 years old and nurses,
whereas women in the Royal College of General Practitioners’ oral contraception study had a
median age of 29 at recruitment. Women in the Oxford Family Planning study were aged 25–39.
In addition, the majority of women used oral contraceptives with 50 mcg of ethinyl estradiol,
which is a higher dose than commonly used today. However, results are reassuring for women
starting combined hormonal contraception today.

A recent large epidemiological study from Denmark studied the effect of modern contraceptives
on breast cancer 43. The study showed similar results to previous studies in increased breast
cancer risk for women with combined hormonal contraception. However, the study showed that
current or recent LNG-IUS use was also associated with a small but significant increase in
receiving a diagnosis of breast cancer with a relative risk of 1.21 (95% CI 1.11–1.33). The 52 mg
LNG-IUS has been shown to be effective in the prevention of endometrial cancer 44. There are
currently no studies which have studied the long-term effect of LNG-IUS or low- or medium-
dose progestin methods on ovarian or colon cancer risk, as these methods have not been on the
market long enough.

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Conclusion
Women in high- as well as low-resource settings experience the social, economic, and health
consequences of unintended pregnancies. High sterilization rates limit women’s reproductive
choices and deny them access to the added benefits of reversible hormonal contraception. Apart
from abortion and birth, which are options women may choose, unintended pregnancy may also
result in ectopic pregnancy, which may threaten health and the future fertility of women.
Women, and to some extent HCPs, are in many cases unaware and need increased information
on the differences in effectiveness of different contraceptive methods and how methods should
be used to improve effectiveness in typical use.

Fear of negative health effects of hormonal contraception remain an obstacle to the use of
effective contraception for many women. Women fear a true but very small increased risk of
breast cancer but remain ignorant of the many proven added health benefits of hormonal
contraception, such as reduction in menstrual blood flow and menstrual pain and protection
against certain cancers. There are also notions that the long-term health effects of hormonal
contraception are somehow unknown and unexplored because of a lack of research. However,
there are several large prospective, retrospective, and epidemiological studies of hormonal
contraception which clearly show that these fears are exaggerated.

New large prospective studies on contraceptive use and especially the use of LNG-IUS and
medium-dose progestin-only contraception and their effects on cancer and mood are lacking.
Efforts should be made to carefully design these studies so that confounders can be controlled.

Reversible hormonal contraception has short-term as well as long-term benefits for women
which deserve more attention from HCPs and women alike. If women are provided with more
nuanced information regarding the risks and benefits of effective reversible contraception, they
may make more informed decisions on the use of effective contraception and gain a higher
quality of life.

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Notes
[version 1; referees: 3 approved]

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Funding Statement
The author is supported by a research grant from Stockholm County Council DNR: K0138-2015.

The funders had no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.
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Notes
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Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and
are edited as a service to readers. In order to make these reviews as comprehensive and
accessible as possible, the referees provide input before publication and only the final, revised
version is published. The referees who approved the final version are listed with their names and
affiliations but without their reports on earlier versions (any comments will already have been
addressed in the published version).

The referees who approved this article are:

 Melanie A Gold, Department of Paediatrics, Columbia University Medical Center, New

York, USA; Department Population and Family Health, Columbia University Mailman
School of Public Health, New York, USA; School Based Health Centers, New York-
Presbyterian Hospital, New York, USA

No competing interests were disclosed.

 Luis Bahamondes, Human Reproduction Unit, Department of Obstetrics and Gynecology,

School of Medicine, University of Campinas (UNICAMP), Capinas, SP, Brazil

No competing interests were disclosed.

 Joseph Speidel, Bixby Center for Global Reproductive Health, Department of Obstetrics,
Gynecology and Reproductive Sciences, University of California, San Francisco, CA,
USA

No competing interests were disclosed.

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References
1. Sedgh G, Singh S, Hussain R: Intended and unintended pregnancies worldwide in 2012 and
recent trends. Stud Fam Plann. 2014;45(3):301–14. 10.1111/j.1728-4465.2014.00393.x [PMC
free article] [PubMed] [Cross Ref]
2. Bearak J, Popinchalk A, Alkema L, et al. : Global, regional, and subregional trends in
unintended pregnancy and its outcomes from 1990 to 2014: estimates from a Bayesian
hierarchical model. Lancet Glob Health. 2018;6(4):e380–e389. 10.1016/S2214-109X(18)30029-
9 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
3. Maguire K, Westhoff C: The state of hormonal contraception today: established and emerging
noncontraceptive health benefits. Am J Obstet Gynecol. 2011;205(4 Suppl):S4–8.
10.1016/j.ajog.2011.06.056 [PubMed] [Cross Ref]
4. United Nations DoEaSA, Population Division: Trends in Contraceptive Use Worldwide
2015.2015. Reference Source
5. Trussell J: Contraceptive failure in the United States. Contraception. 2011;83(5):397–404.
10.1016/j.contraception.2011.01.021 [PMC free article] [PubMed] [Cross Ref]
6. Winner B, Peipert JF, Zhao Q, et al. : Effectiveness of long-acting reversible contraception. N
Engl J Med. 2012;366(21):1998–2007. 10.1056/NEJMoa1110855 [PubMed] [Cross Ref] F1000
Recommendation
7. Peipert JF, Zhao Q, Allsworth JE, et al. : Continuation and satisfaction of reversible
contraception. Obstet Gynecol. 2011;117(5):1105–13. 10.1097/AOG.0b013e31821188ad [PMC
free article] [PubMed] [Cross Ref]
8. Rose SB, Lawton BA: Impact of long-acting reversible contraception on return for repeat
abortion. Am J Obstet Gynecol. 2012;206(1):37.e1–6. 10.1016/j.ajog.2011.06.102 [PubMed]
[Cross Ref]
9. Cameron ST, Glasier A, Chen ZE, et al. : Effect of contraception provided at termination of
pregnancy and incidence of subsequent termination of pregnancy. BJOG. 2012;119(9):1074–80.
10.1111/j.1471-0528.2012.03407.x [PubMed] [Cross Ref] F1000 Recommendation
10. Heikinheimo O, Gissler M, Suhonen S: Age, parity, history of abortion and contraceptive
choices affect the risk of repeat abortion. Contraception. 2008;78(2):149–54.
10.1016/j.contraception.2008.03.013 [PubMed] [Cross Ref]
11. Asker C, Stokes-Lampard H, Beavan J, et al. : What is it about intrauterine devices that
women find unacceptable? Factors that make women non-users: a qualitative study. J Fam
Plann Reprod Health Care. 2006;32(2):89–94. 10.1783/147118906776276170 [PubMed] [Cross
Ref]
12. Envall N, Groes Kofoed N, Kopp-Kallner H: Use of effective contraception 6 months after
emergency contraception with a copper intrauterine device or ulipristal acetate - a prospective
observational cohort study. Acta Obstet Gynecol Scand. 2016;95(8):887–93. 10.1111/aogs.12916
[PubMed] [Cross Ref]
13. Marions L, Lövkvist L, Taube A, et al. : Use of the levonorgestrel releasing-intrauterine
system in nulliparous women--a non-interventional study in Sweden. Eur J Contracept Reprod
Health Care. 2011;16(2):126–34. 10.3109/13625187.2011.558222 [PubMed] [Cross Ref]
14. Gemzell-Danielsson K, Schellschmidt I, Apter D: A randomized, phase II study describing
the efficacy, bleeding profile, and safety of two low-dose levonorgestrel-releasing intrauterine
contraceptive systems and Mirena. Fertil Steril. 2012;97(3):616–22.e1-3.
10.1016/j.fertnstert.2011.12.003 [PubMed] [Cross Ref] F1000 Recommendation
15. Farquhar CM: Ectopic pregnancy. Lancet. 2005;366(9485):583–91. 10.1016/S0140-
6736(05)67103-6 [PubMed] [Cross Ref]
16. Marion LL, Meeks GR: Ectopic pregnancy: History, incidence, epidemiology, and risk
factors. Clin Obstet Gynecol. 2012;55(2):376–86. 10.1097/GRF.0b013e3182516d7b [PubMed]
[Cross Ref]
17. Li C, Zhao WH, Zhu Q, et al. : Risk factors for ectopic pregnancy: a multi-center case-
control study. BMC Pregnancy Childbirth. 2015;15:187. 10.1186/s12884-015-0613-1 [PMC free
article] [PubMed] [Cross Ref] F1000 Recommendation
18. Barnhart KT: Clinical practice. Ectopic pregnancy. N Engl J Med. 2009;361(4):379–87.
10.1056/NEJMcp0810384 [PubMed] [Cross Ref]
19. Rosenstock JR, Peipert JF, Madden T, et al. : Continuation of reversible contraception in
teenagers and young women. Obstet Gynecol. 2012;120(6):1298–305.
10.1097/AOG.0b013e31827499bd [PMC free article] [PubMed] [Cross Ref]
20. Heinemann K, Reed S, Moehner S, et al. : Comparative contraceptive effectiveness of
levonorgestrel-releasing and copper intrauterine devices: the European Active Surveillance
Study for Intrauterine Devices. Contraception. 2015;91(4):280–3.
10.1016/j.contraception.2015.01.011 [PubMed] [Cross Ref]
21. Moini A, Hosseini R, Jahangiri N, et al. : Risk factors for ectopic pregnancy: A case-control
study. J Res Med Sci. 2014;19(9):844–9. [PMC free article] [PubMed]
22. Spona J, Elstein M, Feichtinger W, et al. : Shorter pill-free interval in combined oral
contraceptives decreases follicular development. Contraception. 1996;54(2):71–7.
10.1016/0010-7824(96)00137-0 [PubMed] [Cross Ref]
23. Klipping C, Duijkers I, Trummer D, et al. : Suppression of ovarian activity with a
drospirenone-containing oral contraceptive in a 24/4 regimen. Contraception. 2008;78(1):16–25.
10.1016/j.contraception.2008.02.019 [PubMed] [Cross Ref]
24. Christin-Maitre S, Serfaty D, Chabbert-Buffet N, et al. : Comparison of a 24-day and a 21-
day pill regimen for the novel combined oral contraceptive, nomegestrol acetate and 17β-
estradiol (NOMAC/E2): a double-blind, randomized study. Hum Reprod. 2011;26(6):1338–47.
10.1093/humrep/der058 [PubMed] [Cross Ref]
25. Dinger J, Minh TD, Buttmann N, et al. : Effectiveness of oral contraceptive pills in a large
U.S. cohort comparing progestogen and regimen. Obstet Gynecol. 2011;117(1):33–40.
10.1097/AOG.0b013e31820095a2 [PubMed] [Cross Ref]
26. Edelman A, Micks E, Gallo MF, et al. : Continuous or extended cycle vs. cyclic use of
combined hormonal contraceptives for contraception. Cochrane Database Syst Rev. 2014;
(7):CD004695. 10.1002/14651858.CD004695.pub3 [PubMed] [Cross Ref] F1000
Recommendation
27. Jensen JT, Garie SG, Trummer D, et al. : Bleeding profile of a flexible extended regimen of
ethinylestradiol/drospirenone in US women: an open-label, three-arm, active-controlled,
multicenter study. Contraception. 2012;86(2):110–8. 10.1016/j.contraception.2011.12.009
[PubMed] [Cross Ref]
28. Sulak PJ, Smith V, Coffee A, et al. : Frequency and management of breakthrough bleeding
with continuous use of the transvaginal contraceptive ring: a randomized controlled trial. Obstet
Gynecol. 2008;112(3):563–71. 10.1097/AOG.0b013e3181842071 [PubMed] [Cross Ref] F1000
Recommendation
29. Jensen JT, Parke S, Mellinger U, et al. : Effective treatment of heavy menstrual bleeding with
estradiol valerate and dienogest: a randomized controlled trial. Obstet Gynecol.
2011;117(4):777–87. 10.1097/AOG.0b013e3182118ac3 [PubMed] [Cross Ref] F1000
Recommendation
30. Fraser IS, McCarron G: Randomized trial of 2 hormonal and 2 prostaglandin-inhibiting
agents in women with a complaint of menorrhagia. Aust N Z J Obstet Gynaecol. 1991;31:66–70.
10.1111/j.1479-828X.1991.tb02769.x [PubMed] [Cross Ref]
31. Mansour D, Verhoeven C, Sommer W, et al. : Efficacy and tolerability of a monophasic
combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol in a 24/4
regimen, in comparison to an oral contraceptive containing ethinylestradiol and drospirenone in a
21/7 regimen. Eur J Contracept Reprod Health Care. 2011;16(6):430–43.
10.3109/13625187.2011.614029 [PMC free article] [PubMed] [Cross Ref] F1000
Recommendation
32. Lethaby A, Hussain M, Rishworth JR, et al. : Progesterone or progestogen-releasing
intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2015; (4):
CD002126. 10.1002/14651858.CD002126.pub3 [PubMed] [Cross Ref] F1000 Recommendation
33. McNicholas C, Swor E, Wan L, et al. : Prolonged use of the etonogestrel implant and
levonorgestrel intrauterine device: 2 years beyond Food and Drug Administration-approved
duration. Am J Obstet Gynecol. 2017;216(6):586.e1–586.e6. 10.1016/j.ajog.2017.01.036 [PMC
free article] [PubMed] [Cross Ref] F1000 Recommendation
34. Heikinheimo O, Gemzell-Danielsson K: Emerging indications for the levonorgestrel-
releasing intrauterine system (LNG-IUS). Acta Obstet Gynecol Scand. 2012;91(1):3–9.
10.1111/j.1600-0412.2011.01303.x [PubMed] [Cross Ref]
35. Bixo M, Johansson M, Timby E, et al. : Effects of GABA active steroids in the female brain
with a focus on the premenstrual dysphoric disorder. J Neuroendocrinol. 2018;30(2).
10.1111/jne.12553 [PubMed] [Cross Ref]
36. Freeman EW, Halbreich U, Grubb GS, et al. : An overview of four studies of a continuous
oral contraceptive (levonorgestrel 90 mcg/ethinyl estradiol 20 mcg) on premenstrual dysphoric
disorder and premenstrual syndrome. Contraception. 2012;85(5):437–45.
10.1016/j.contraception.2011.09.010 [PubMed] [Cross Ref]
37. Lopez LM, Kaptein AA, Helmerhorst FM: Oral contraceptives containing drospirenone for
premenstrual syndrome. Cochrane Database Syst Rev. 2009; (2):CD006586.
10.1002/14651858.CD006586.pub3 [PubMed] [Cross Ref]
38. Lundin C, Danielsson KG, Bixo M, et al. : Combined oral contraceptive use is associated
with both improvement and worsening of mood in the different phases of the treatment cycle-A
double-blind, placebo-controlled randomized trial. Psychoneuroendocrinology. 2017;76:135–43.
10.1016/j.psyneuen.2016.11.033 [PubMed] [Cross Ref] F1000 Recommendation
39. Iversen L, Sivasubramaniam S, Lee AJ, et al. : Lifetime cancer risk and combined oral
contraceptives: the Royal College of General Practitioners' Oral Contraception Study. Am J
Obstet Gynecol. 2017;216(6):580.e1–580.e9. 10.1016/j.ajog.2017.02.002 [PubMed] [Cross Ref]
F1000 Recommendation
40. Zhu H, Lei X, Feng J, et al. : Oral contraceptive use and risk of breast cancer: a meta-analysis
of prospective cohort studies. Eur J Contracept Reprod Health Care. 2012;17(6):402–14.
10.3109/13625187.2012.715357 [PubMed] [Cross Ref]
41. Vessey M, Yeates D: Oral contraceptive use and cancer: final report from the Oxford-Family
Planning Association contraceptive study. Contraception. 2013;88(6):678–83.
10.1016/j.contraception.2013.08.008 [PubMed] [Cross Ref]
42. Charlton BM, Rich-Edwards JW, Colditz GA, et al. : Oral contraceptive use and mortality
after 36 years of follow-up in the Nurses' Health Study: prospective cohort study. BMJ.
2014;349:g6356. 10.1136/bmj.g6356 [PMC free article] [PubMed] [Cross Ref] F1000
Recommendation
43. Mørch LS, Skovlund CW, Hannaford PC, et al. : Contemporary Hormonal Contraception and
the Risk of Breast Cancer. N Engl J Med. 2017;377(23):2228–39. 10.1056/NEJMoa1700732
[PubMed] [Cross Ref] F1000 Recommendation
44. Beining RM, Dennis LK, Smith EM, et al. : Meta-analysis of intrauterine device use and risk
of endometrial cancer. Ann Epidemiol. 2008;18(6):492–9. 10.1016/j.annepidem.2007.11.011
[PubMed] [Cross Ref] F1000 Recommendation