TUGAS MATA KULIAH

CRITICAL ANALYSIS

“ Levonorgestrel-releasing intrauterine system and breast cancer risk: A systematic

review and meta-analysis”

Dosen Pengampu : Evi Pratami, S.ST., M.Keb

Disusun oleh :

BHAYANTI ISDWARA
NIM. P27824419008

KEMENTERIAN KESEHATAN R.I

DIREKTORAT JENDERAL TENAGA KESEHATAN
POLITEKNIK KESEHATAN KEMENKES SURABAYA
JURUSAN KEBIDAN
PROGRAM STUDI PROFESI BIDAN
TAHUN 2023
 KATA PENGANTAR

Puji dan syukur kami panjatkan kehadirat Allah SWT atas rahmat dan karunia-
Nya lah sehingga tugas makalah mata kuliah critical analysis dapat terselesaikan dengan
baik tepat pada waktunya. Makalah ini dapat terselesaikan oleh karena bantuan dari pihak
yang terlibat. Oleh karena itu penulis mengucapkan terimakasih kepada pihak – pihak
yang terlibat diantaranya :

1. Dwi Wahyu Wulan, SST., M. Keb, selaku Ketua Jurusan Kebidanan Kampus
Poltekkes Kemenkes Surabaya.
2. Uswatun Khasanah, SST., M. Keb, selaku Ketua Prodi Profesi Bidan Poltekkes
Kemenkes Surabaya.
3. Evi Pratami, S.ST., M. Keb, selaku dosen pengampu mata kuliah Critical Analysis
Poltekkes Kemenkes Surabaya.
4. Seluruh pihak yang turut membantu dan kerjasama dalam menyelesaikan makalah
ini.

Saya menyadari bahwa laporan ini masih memiliki banyak kekurangan baik isi
maupun teknik penulisan. Untuk itu kritik dan saran sangat diperlukan untuk perbaikan.

Surabaya, 17 Juli 2023

Penyusun
 BAB 1
PENDAHULUAN

1.1 Latar Belakang

Dengan 2,3 juta kasus baru per tahun di seluruh dunia, BC adalah kanker yang paling
umum di kalangan wanita. Untungnya, angka kematian menurun karena penerapan
skrining dan terapi yang ditingkatkan selama dekade terakhir. Banyak hal yang menjadi
faktor risiko kanker payudara, antara lain jarak yang lama antara menarke dan
menopause, ada keluarga yang memiliki riwayat kanker payudara, obesitas dan diet tinggi
lemak, usia produktif ke atas, hamil pertama di usia tua, dan hormon. Berbagai faktor
risiko diketahui termasuk usia, faktor genetik, kepadatan payudara, jumlah kelahiran,
konsumsi alkohol, seperti erta paparan hormon endogen dan eksogen mis. dalam konteks
terapi penggantian hormon (HRT) atau kontrasepsi.

Hormon diduga ikut meningkatkan risiko kanker payudara lebih sebagai promotor
daripada inisiator. Hormon yang dimaksud adalah paparan hormon seks seperti estrogen
dan progesteron yang berlebihan sehingga mengganggu proses fisiologis dalam tubuh,
termasuk jaringan mammae. Dalam kehidupan sehari-hari, ternyata estrogen,
progesteron, maupun kombinasi keduanya banyak dikonsumsi oleh masyarakat, terutama
wanita. Salah satu contoh dari penggunaan hormon estrogen dan progesteron adalah
kontrasepsi hormonal yang digunakan sebagai salah satu alat kontrasepsi. Prevalensi
kanker payudara yang tinggi dan teori tentang paparan hormon estrogen serta progesteron
sebagai salah satu faktor risiko kanker payudara melatarbelakangi penelitan untuk
mengetahui hubungan antara pemakaian KB hormonal dengan kejadian kanker payudara.
Mengenai hormon replacement therapy (HRT), sudah ada cukup banyak informasi yang
tersedia: data WHI jangka panjang menunjukkan penurunan risiko BC secara signifikan
dengan HRT estrogen saja. Sementara itu, wanita yang menggunakan hormon
replacement therapy (HRT) kombinasi estrogen dan progestogen memiliki peningkatan
risiko didiagnosis dengan breast cancer (BC).
1.2 Tujuan

1.2.1 Tujuan Umum

Makalah ini bertujuan untuk melakukan critical analysis jurnal yang berjudul
“Levonorgestrel-releasing intrauterine system and breast cancer risk: A systematic
review and meta-analysis”

1.2.2 Tujuan Khusus

1. Mampu melakukan analisis jurnal berdasarkan clarity
2. Mampu melakukan analisis jurnal berdasarkan accuracy
3. Mampu melakukan analisis jurnal berdasarkan percision
4. Mampu melakukan analisis jurnal berdasarkan consistency
5. Mampu melakukan analisis jurnal berdasarkan relevant
6. Mampu melakukan analisis jurnal berdasarkan significance
7. Mampu melakukan analisis jurnal berdasarkan logicalness
8. Mampu melakukan analisis jurnal berdasarkan depth
9. Mampu melakukan analisis jurnal berdasarkan breadth
10. Mampu melakukan analisis jurnal berdasarkan fairness
1.3 Manfaat
1. Meningkatkan kemampuan mahasiswa pendidikan profesi bidan dalam menerapkan
critical thinking.
2. Meningkatkan kemampuan mahasiswa khususnya mahasiswa pendidikan profesi
bidan dalam menerapkan critical thinking pada bedah jurnal dengan pendekatan
nilai – nilai intelektual.
3. Memperluas informasi dan pengetahuan mahasiswa profesi bidan dengan
menggunakan jurnal terbaru.
 BAB 2
ISI

2.1 Clarity (Kejelasan)

1. Nama Jurnal : Acta Obstet Gynecol Scand
2. Judul Artikel : Levonorgestrel-releasing intrauterine system and
breast cancer risk: A systematic review and meta-analysis
3. Rumusan masalah : Adakah hubungan antara penggunaan LNG-IUS
dan risiko kanker payudara?
4. Tujuan : untuk menganalisis secara sistematis meninjau
hubungan antara penggunaan LNG – IUS dan risiko kanker payudara secara
nyata.
5. Prevalensi : Penggunaan sistem intrauterin yang melepaskan
levonorgestorgest 52 mg dapat dikaitkan dengan peningkatan risiko kanker
payudara, dan risiko ini lebih tinggi pada pengguna yang lebih tua.
6. Data yang memperkuat : Studi ini terdaftar di PROSPERO
(CRD42017059076).
2.2 Accuracy (akurasi)
1. Nilai schimago : Q1

2. Nama jurnal : Acta Obstet Gynecol Scand

3. Tahun terbit : 2023
4. Link jurnal :
https://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1111/aogs.13817
2.3 Precision (presisi)
1. Pendahuluan singkat
Studi epidemiologi besar telah menunjukkan bahwa beberapa metode kontrasepsi
hormonal dikaitkan dengan peningkatan risiko kanker payudara, terutama jika digunakan
dalam jangka waktu lama.1-4Sistem intrauterin pelepas levonorgestrel 52 mg (LNG-IUS)
adalah kontrasepsi yang sangat efektif, disetujui untuk penggunaan hingga 5 tahun. LNG-
IUS mengirimkan levonorgestrel (LNG) ke endometrium, sehingga mengurangi paparan
sistemik terhadap LNG. Selain itu, alat ini telah berhasil digunakan untuk pengobatan
perdarahan menstruasi berat dan perlindungan endometrium selama terapi estrogen
berkelanjutan pada wanita pascamenopause. Alat ini digunakan oleh wanita yang mencari
kontrasepsi reversibel jangka panjang, yang berarti paparan LNG dapat berlanjut selama
bertahun-tahun, meskipun dalam konsentrasi kecil. Data menunjukkan bahwa konsentrasi
LNG di dalam rahim 1000 kali lebih tinggi daripada di dalam plasma.
Persyaratan untuk progesteron dalam perkembangan kelenjar susu yang normal
sudah mapan, namun, peran hormon ini dalam karsinogenesis payudara masih belum
jelas. Studi yang meneliti efek progestin pada garis sel kanker payudara manusia telah
menunjukkan respons seluler bifasik terhadap progesteron: paparan awal terhadap
hormon steroid menghasilkan ledakan proliferatif, sedangkan paparan yang berkelanjutan
mengakibatkan penghambatan pertumbuhan. Temuan ini sesuai dengan yang diterbitkan
oleh penulis lain, yang menyatakan bahwa progestogen dapat bertindak sebagai agen
proliferatif dan antiproliferatif dalam jaringan payudara. Oleh karena itu, semakin banyak
bukti yang menunjukkan bahwa kunci untuk memahami data yang tidak konsisten
tentang efek seluler progestogen terletak pada durasi dan pola paparan progestogen.
Hubungan antara penggunaan LNG-IUS dan risiko kanker payudara merupakan
kemungkinan teoretis yang saat ini diperdebatkan dalam literatur medis. Tujuan kami
adalah untuk secara sistematis meninjau bukti pada subjek. Selanjutnya, untuk
mendapatkan ukuran efek yang konsisten dari asosiasi potensial penggunaan LNG-IUS
52 mg dan risiko kanker payudara, kami melakukan meta-analisis studi kunci yang
menggunakan metode yang tepat untuk menyelidiki subjek.
2. Metode penelitian singkat
a) Rancangan penelitian : tinjauan sistematis dan meta-analisis.
b) Sampel : literatur peer-review tentang subjek yang diterbitkan dari 10 Januari 1999
hingga 31 Juli 2019. Kami menggunakan kombinasi istilah Medical Subject
 Headings (MeSH) untuk LNG-IUS dan risiko kanker payudara (neoplasma payudara,
kanker payudara, tumor payudara , karsinoma payudara, sistem levonorgestrel,
Mirena, alat kontrasepsi, alat progestin, alat kontrasepsi progestin).
c) Pengumpulan data : pengambilan data dari literatur yang telah ada dengan
berdasarkan kriteria inklusi dan kriteria eksklusi yang telah ditetapkan.
3. Hasil
Mengidentifikasi 96 studi dan referensi silang secara manual dan mengecualikan
artikel duplikat. Tujuh puluh artikel dikeluarkan setelah penerapan kriteria inklusi
dan eksklusi, menghasilkan penilaian 26 artikel teks lengkap. Delapan studi
dianggap cocok untuk dimasukkan dalam ulasan ini. Tiga dari makalah yang
dipilih adalah studi kasus-kontrol 12,14,15 sedangkan 5 adalah studi kohort 11,16-
19 Empat di antaranya dilakukan di Finlandia 11,12,14,161 di Jerman 151 di
Denmark,191 di Norwegia 17 dan 1 di Israel 18.

A. Tinjauan sistematis studi yang membahas penggunaan LNG-IUS dan risiko

kanker payudara
Empat dari 8 penelitian dalam ulasan ini melaporkan peningkatan risiko
kanker payudara pada wanita yang menggunakan LNG-
IUS.12,14,16,19Mengambil non-pengguna LNG-IUS pada populasi wanita
umum Finlandia sebagai referensi untuk standar. Mørch et al19menerbitkan
sebuah penelitian berdasarkan data dari 1,8 juta wanita Denmark yang
ditindaklanjuti selama rata-rata 10,9 tahun. Wanita yang menggunakan LNG-
IUS pada saat pengumpulan data (pengguna saat ini) atau yang melaporkan
penggunaan kontrasepsi baru-baru ini memiliki risiko lebih tinggi terkena
kanker payudara dibandingkan wanita yang tidak pernah menggunakan
kontrasepsi hormonal. Data dari 503.441 wanita-tahun yang menggunakan
LNG-IUS menunjukkan RR sebesar 1,21 (95% CI 1,11-1,33). Mørch et al
melaporkan 571 kasus kanker payudara di antara pengguna LNG-IUS. Studi
kohort prospektif berbasis di Norwegia (NOWAC—Norwegian Women and
Cancer study)17mencatat data dari 9144 pengguna LNG-IUS dan 95 174 non-
pengguna. Setelah 12,5 tahun, 297 kasus kanker payudara dilaporkan. RR
kanker payudara pada pengguna LNG-IUS adalah 1,03 (95% CI 0,91-1,17)
 dan indeks massa tubuh (BMI), tingkat aktivitas fisik, riwayat kanker
payudara ibu, dan status menopause dipertimbangkan dalam analisis.
B. Meta analisis
Tujuh dari 8 studi yang ditinjau memiliki data lengkap tentang jumlah pengguna dan
non-pengguna LNG-IUS dan risiko kanker payudara setelah insersi LNG-IUS. Tiga
adalah studi kasus-kontrol dan 4 adalah studi kohort. Model meta-analisis kami
dibangun menggunakan data yang berasal dari hasil asli yang dilaporkan dalam
penelitian. Kami mengelompokkan analisis berdasarkan strata usia wanita yang
termasuk dalam setiap makalah ( <50 tahun, ≥ 50 tahun, dan campuran ) Karena
heterogenitas studi (SAYA2= 78%), terutama di antara penelitian yang melaporkan
pasien berusia <50 tahun kami menggunakan model efek acak. Dengan
menstandarkan ukuran efek dari semua studi dan menggabungkan hasil dari 7 studi
ini, meta-analisis menunjukkan peningkatan risiko kanker payudara pada pengguna
LNG-IUS: usia <50 tahun , OR = 1,12 (95% CI 1,02-1,22, SAYA2= 66%,P= .02);
usia ≥50 tahun OR = 1,52 (95% CI 1,34-1,72, SAYA2= 0%,P= .84). Untuk semua
wanita, meta-analisis menunjukkan peningkatan risiko kanker payudara pada
pengguna LNG-IUS (OR = 1,16, 95% CI 1,06-1,28,SAYA2= 78%,P< .01).
C. Mengontrol faktor risiko kanker payudara yang diketahui
Pengendalian faktor-faktor yang mempengaruhi kejadian kanker payudara
(pendidikan, status sosial ekonomi, faktor reproduksi dan hormon, riwayat kanker
payudara sebelumnya, penggunaan alkohol, peningkatan IMT)20sangat bervariasi di
antara studi yang termasuk dalam meta-analisis ini. Dinger et al15 dianggap sebagai
faktor risiko potensial untuk kanker payudara, termasuk BMI, riwayat kanker
payudara dalam keluarga, usia pertama kali melahirkan, usia menarche, dan aktivitas
fisik. Heikkinen dkk12menyesuaikan hasil untuk tahun kelahiran, penggunaan
kontrasepsi hormonal dan HT sebelumnya, usia saat menarche, paritas, riwayat
kanker payudara dalam keluarga, BMI, tahun bersekolah, merokok, dan penggunaan
alkohol. Lyytinen et al14mampu mengontrol hanya untuk usia saat kelahiran pertama
dan paritas. Jareid et al17usia yang teridentifikasi pada awal tindak lanjut, BMI,
tingkat aktivitas fisik saat pendaftaran, ibu riwayat kanker payudara, usia saat
menarche, pernah menggunakan OC, paritas, dan status menopause pada awal tindak
lanjut.
4. Gambar dan tabel
A. Gambar
1. Gambar 1 : Diagram alur PRISMA.

2. Gambar 2 : Meta-analisis Plot Hutan

3. Gambar 3 : Plot corong

B. Tabel
1. Tabel 1 : Ringkasan studi yang disertakan

2.4 Konsistensi
Studi ini terdaftar di PROSPERO (CRD42017059076).
2.5 Relevan
Penelitian ini memiliki relevan yang sedang untuk lingkungan sekitar saya.
2.6 Bermakna (signifikan)
Penggunaan sistem intrauterin yang melepaskan levonorgestorgest 52 mg dapat
dikaitkan dengan peningkatan risiko kanker payudara, dan risiko ini lebih tinggi
pada pengguna yang lebih tua.
2.7 Logicalness
Menurut jurnal tersebut didapatkan tinjauan sistematis dan meta-analisis ini
mengarah pada peningkatan risiko kanker payudara di antara pengguna LNG-IUS,
terutama untuk wanita berusia 50 tahun atau lebih.
2.8 Kedalaman (depth)
Tujuan umum dari jurnal tersebut adalah untuk menganalisis secara sistematis
meninjau hubungan antara penggunaan LNG – IUS dan risiko kanker payudara
secara nyata.
Selain tujuan umum dalam jurnal memiliki tujuan khusus diantaranya yakni :
1. Untuk mengevaluasi hubungan antara penggunaan LNG-IUS dan risiko
perkembangan kanker payudara.
2.9 Keluasan
Data dari 503.441 wanita-tahun yang menggunakan LNG-IUS menunjukkan RR
sebesar 1,21 (95% CI 1,11-1,33). Mørch et al melaporkan 571 kasus kanker payudara
di antara pengguna LNG-IUS. Studi kohort prospektif berbasis di Norwegia
(NOWAC—Norwegian Women and Cancer study)17mencatat data dari 9144
pengguna LNG-IUS dan 95 174 non-pengguna. Setelah 12,5 tahun, 297 kasus kanker
payudara dilaporkan. RR kanker payudara pada pengguna LNG-IUS adalah 1,03 (95%
CI 0,91-1,17) dan indeks massa tubuh (BMI), tingkat aktivitas fisik, riwayat kanker
payudara ibu, dan status menopause dipertimbangkan dalam analisis. 7 studi ini, meta-
analisis menunjukkan peningkatan risiko kanker payudara pada pengguna LNG-IUS:
usia <50 tahun , OR = 1,12 (95% CI 1,02-1,22, SAYA2= 66%,P= .02); usia ≥50 tahun
OR = 1,52 (95% CI 1,34-1,72, SAYA2= 0%,P= .84). Untuk semua wanita, meta-
analisis menunjukkan peningkatan risiko kanker payudara pada pengguna LNG-IUS
(OR = 1,16, 95% CI 1,06-1,28,SAYA2= 78%,P< .01).

2.10 Keadilan
Tidak dilaporkan setelah periode paparan bentuk kontrasepsi hormonal lainnya,
biasanya kontrasepsi oral kombinasi.Oleh karena itu, jika tidak ada atau hanya
terdapat kesenjangan yang sangat kecil antara penggunaan kontrasepsi hormonal
sebelumnya dan pemasangan IUS, maka akan sulit untuk membedakan kemungkinan
efek biologis dari LNG-IUS itu sendiri dari efek kontrasepsi hormonal sebelumnya.
 BAB 3
PEMBAHASAN

Tinjauan sistematis dan meta-analisis ini mengarah pada peningkatan risiko

kanker payudara di antara pengguna LNG-IUS, terutama untuk wanita berusia 50 tahun
atau lebih. Yang penting, tidak ada data acak untuk wanita yang menggunakan LNG-IUS
vs mereka yang menggunakan metode lain. Selain itu, studi dalam meta-analisis ini
mencakup kohort wanita yang menggunakan LNG-IUS untuk berbagai alasan, termasuk
kontrasepsi, perdarahan abnormal, perlindungan endometrium, dan alasan medis lainnya.
Kami memperoleh perkiraan risiko terpisah untuk wanita menurut strata usia yang
berbeda, yang memungkinkan kami melakukan meta-analisis bertingkat. Metaanalisis
dengan jelas menunjukkan bahwa risiko kanker payudara meningkat sejalan dengan strata
usia pengguna LNG-IUS. Faktanya, dalam meta-analisis, hanya 2 dari 5 penelitian yang
melaporkan wanita berusia. Risiko kanker payudara pada wanita yang lebih tua adalah
diperiksa dalam 212,14dari 8 studi11,12,14-19 termasuk dalam tinjauan ini, dan kedua
penelitian menunjukkan bahwa wanita yang lebih tua (umumnya, pascamenopause) yang
menggunakan LNG-IUS untuk alasan selain kontrasepsi memiliki risiko kanker payudara
yang lebih tinggi.

Penting untuk dicatat bahwa beberapa faktor risiko kanker payudara mungkin
relatif umum pada wanita dengan indikasi klinis untuk penggunaan LNG-IUS
perimenopause/pascamenopause. Perdarahan yang tidak normal dan perdarahan
menstruasi yang banyak merupakan indikasi penggunaan LNG-IUS,22dan kondisi ini
lebih sering terjadi pada wanita gemuk yang berisiko tinggi terkena kanker payudara
karena anovulasi atau ovulasi abnormal dalam waktu lama.23Faktor lain yang
berhubungan serupa adalah kondisi hipoestrogenik dan kegagalan ovarium prematu
 BAB 4
SIMPULAN DAN SARAN

4.1 Simpulan
Kami memperoleh bukti yang menunjukkan adanya hubungan antara risiko
kanker payudara dan penggunaan LNG-IUS pada usia berapa pun dan untuk
indikasi apa pun. Namun, isu-isu metodologis di seluruh studi yang tersedia
mungkin menimbulkan keraguan tentang hubungan ini, dan kekhawatiran
tentang masalah yang melekat untuk mempelajari isu yang begitu kompleks
di kelompok perempuan yang berbeda tentu saja patut dipertimbangkan. Jika
analisis kami valid, risiko kanker payudara yang disebabkan kemungkinan
besar kecil untuk pengguna LNG-IUS premenopause; namun, untuk wanita
yang berusia lebih dari 50 tahun, mungkin ada peningkatan risiko kanker
payudara hampir 40%. Mengingat bukti yang menunjukkan hubungan antara
kontrasepsi hormonal dan HT dengan risiko kanker payudara, sulit dipercaya
bahwa penggunaan LNG-IUS mungkin tanpa risiko onkologis. Oleh karena
itu, pengguna LNG-IUS harus menyadari tren ini.
4.2 Saran

1. Diharapkan tenaga kesehatan khususnya bidan dapat menerapkan critical

thinking dalam pelayanan kesehatan kebidanan sehingga terwujudnya

pelayanan yang berkualitas.

2. Diharapkan dengan adanya studi lanjutan mengenai apakah penggunaan

LNG-IUS aman dari sudut pandang onkologi masih belum terselesaikan.

 | |
Received: 8 January 2019    Revised: 18 January 2020    Accepted: 20 January 2020

DOI: 10.1111/aogs.13817

S Y S T E M AT I C R E V I E W

Levonorgestrel-releasing intrauterine system and breast cancer

risk: A systematic review and meta-analysis

Livia Conz1,2  | Bruna Salani Mota3  | Luis Bahamondes1  | Maíra Teixeira Dória1,2  |

Sophie Françoise Mauricette Derchain1,2  | Rachel Rieira4  | Luis Otavio Sarian1,2

1
Department of Obstetrics and Gynecology,
University of Campinas Medical School
(UNICAMP), Campinas, Sao Paulo, Brazil
2
Division of Gynecologic and Breast
Oncology, Women’s Hospital (CAISM),
UNICAMP, Campinas, Sao Paulo, Brazil
3
Setor de Mastologia da Clinica Ginecológica
do ICESP - Instituto do Câncer do estado de
São Paulo, Hospital das Clínicas, Faculdade
de Medicina da Universidade de São Paulo -
FMUSP, Sao Paulo, Brazil
4
Universidade Federal de São Paulo -
UNIFESP, Center of Health Tecnology,
Hospital Sírio Libanês, Sao Paulo, Brazil
Correspondence
Luis Otávio Sarian, Department of
Obstetrics and Gynecology, University of
Campinas Medical School, (UNICAMP),
Campinas, Sao Paulo, Brazil.
Email: sarian@unicamp.br
Funding information
This study received partial financial support
from the Fundação de Apoio à Pesquisa
do Estado de São Paulo (FAPESP; award
no. 2015/20504-9). Luis Sarian received a
research stipend from the Brazilian National
Council for Scientific and Technological
Development (CNPq 308888/2017-0).
Abstract
Introduction: Epidemiological studies have shown that some hormonal contracep-
tive methods are associated with increased breast cancer risk, especially if used over
long periods. Our objective was to conduct a systematic review and meta-analysis of
the literature on the risk of breast cancer development in women using the 52-mg
levonorgestrel-releasing intrauterine system (LNG-IUS).
Material and methods: We performed a thorough review of peer-reviewed publica-
tions from 10 January 1999, through 31 July 2019, using combinations of search terms
for breast cancer risk and LNG-IUS in the Medline, EMBASE, LILACS (Latin American
and Caribbean Health Sciences Literature), and Scielo databases. This review was
registered in PROSPERO (CRD42017059076). Studies reporting breast cancer risk
estimates among healthy users of LNG-IUS were included according to the PRISMA
(Preferred Reporting Items for Systematic Reviews and Meta-analysis) criteria. Two
authors performed data extraction, and a third author resolved disagreements. The
quality of evidence was evaluated using the Downs and Black instrument. A funnel
plot was generated, and a linear regression test of funnel plot asymmetry was used
to assess publication bias. Finally, we performed a random-effects model (owing to
high study heterogeneity) meta-analysis of seven suitable studies, stratified by the
age distribution of patients (<50 years, ≥50 years, and mixed).
Results: We identified 96 studies and manually cross-referenced and excluded duplicate
articles. Seventy articles were excluded on the basis of the inclusion and exclusion cri-
teria, resulting in the assessment of 26 full-text articles. Eight articles were considered
adequate for inclusion in this systematic review, and seven studies were included in the
meta-analysis. Three publications were case-control studies and five were cohort stud-
ies. According to the Downs and Black instrument, 5 studies were rated as “good” and
three studies were deemed “fair”. Our meta-analysis results indicated increased breast
cancer risk in LNG-IUS users: for all women, odds ratio (OR) = 1.16 (95% CI 1.06-1.28,
I2 = 78%, P < .01); for women aged <50 years, OR = 1.12 (95% CI 1.02-1.22, I2 = 66%,
P = .02); and for women aged ≥50 years, OR = 1.52 (95% CI 1.34-1.72, I2 = 0%, P = .84).

Abbreviations: BMI, body mass index; CI, confidence interval; Cu-IUD, copper intrauterine device; HT, hormonal therapy; IUS, intrauterine system; LNG, levonorgestrel; LNG-IUS,
levonorgestrel-releasing intrauterine system; MeSH, medical subject headings; OC, oral contraceptive; OR, odds ratio; RR, relative risk; SIR, standardized incidence ratio.

© 2020 Nordic Federation of Societies of Obstetrics and Gynecology

|
970     
wileyonlinelibrary.com/journal/aogs Acta Obstet Gynecol Scand. 2020;99:970–982.
 |

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CONZ et al.       971

Conclusions: Current evidence suggests that LNG-IUS users have an increased breast
cancer risk regardless of age and indication. The effect of LNG-IUS on breast can-
cer risk seems to be larger in older users. However, our systematic review detected
methodological issues across the available studies, and confounding factors may be
responsible for at least a fraction of the risk effects associated with LNG-IUS use.
Nevertheless, users of LNG-IUS should be aware of these trends. We believe that
caution is needed, and risks should be balanced against proven health benefits (eg
effective treatment of heavy menstrual bleeding and avoidance of surgical inter-
ventions), when prescribing LNG-IUS for long periods of use, especially in women
with other known breast cancer risk factors such as old age, obesity, and familial
predisposition.

KEYWORDS

breast cancer, contraception, dysmenorrhea, levonorgestrel, levonorgestrel-releasing

intrauterine system, menopause

1 |  I NTRO D U C TI O N
Large epidemiological studies have shown that some hormonal
contraceptive methods are associated with an increased risk for
breast cancer, mainly if used over long periods.1-4 The 52-mg lev-
onorgestrel-releasing intrauterine system (LNG-IUS) is a highly ef-
fective contraceptive, approved for up to 5 years of use. LNG-IUS
delivers levonorgestrel (LNG) to the endometrium, thereby reducing
systemic exposure to LNG.1-4 In addition, the device has been suc-
cessfully used for the treatment of heavy menstrual bleeding and
for endometrial protection during continuous estrogen therapy in
postmenopausal women. The device is used by women seeking long-
term, reversible contraception, which means that exposure to LNG
could continue for many years, albeit in small concentrations. Data
have shown that the LNG concentration inside the uterus is 1000
times higher than that in the plasma.5
The requirement for progesterone in normal mammary gland devel-
6
opment is well established; however, the role of this hormone in breast
carcinogenesis remains poorly defined.7 Studies examining the effects
of progestins in human breast cancer cell lines have shown a biphasic
cellular response to progesterone: initial exposure to the steroid hor-
mone resulted in a proliferative burst, whereas sustained exposure re-
sulted in growth inhibition.8 These findings are in agreement with those
published by other authors, who suggested that progestogens can act
both as a proliferative and an antiproliferative agent in breast tissue.9
Therefore, there is a growing body of evidence suggesting that the key
to understanding the inconsistent data about the cellular effects of pro-
gestogens lies in the duration and patterns of progestogen exposure.10
The association between the use of LNG-IUS and breast can-
cer risk is a theoretical possibility that is currently debated in the
medical literature. Our objective was to systematically review the
evidence on the subject. Further, in order to derive a consistent ef-
fect measure of the potential association of 52-mg LNG-IUS use and
Key Message
Current data suggest that use of the 52-mg levonorgestrel-
releasing intrauterine system may be associated with in-
creased risk of developing breast cancer, and this risk is
higher in older users.
breast cancer risk, we performed a meta-analysis of key studies that
used appropriate methods of investigating the subject.
2 | M ATE R I A L A N D M E TH O DS
We conducted a systematic review and a meta-analysis to evaluate
the association between LNG-IUS use and the risk of breast cancer
development. We thoroughly reviewed the peer-reviewed litera-
ture on the subject published from 10 January 1999 through 31 July
2019. We used a combination of Medical Subject Headings (MeSH)
terms for LNG-IUS and breast cancer risk (breast neoplasms, breast
cancer, breast tumor, breast carcinoma, levonorgestrel system,
Mirena, intrauterine device, progestin device, progestin intrauter-
ine device). The primary and secondary outcomes were the occur-
rences of invasive and in situ breast cancer, respectively.
2.1 | Inclusion criteria
We included studies on the association of breast cancer risk and use
of 52-mg LNG-IUS. We stratified the studies or the reported risk ratios
according to the patients’ age strata (<50 years, ≥50 years, and mixed).
 |
972       CONZ et al.
2.2 | Exclusion criteria
Duplicate papers, duplicated data, and manuscripts without origi-
nal data (eg, comments, reviews, case reports, and technical de-
scriptions) were considered ineligible. In the review and analyses,
we avoided including data from patients known to be at a high risk
for breast cancer (eg, with familial risk, with known mutations) and
those with a previous history of breast cancer.
2.3 | Search strategy
This review was performed in accordance with the guidelines de-
scribed in Preferred Reporting Items for Systematic Reviews and Meta-
analyses (PRISMA); International prospective register of Systematic
Reviews (PROSPERO) registration code: CRD42017059076. We per-
formed searches in the electronic databases of Medline (via PubMed),
EMBASE (via OVID), LILACS (Latin American and Caribbean Health
Sciences Literature; via BVS—Biblioteca Virtual en Salud), and Scielo,
using combinations of the following terms: levonorgestrel, levonorg-
estrel-releasing intrauterine system, breast neoplasm, breast cancer,
breast neoplasm risk, and Mirena.
2.4 | Study selection
Records that potentially met the inclusion criteria of this review were
selected for the analysis of their full texts. In case of any disagreement
among the reviewers, a third reviewer was summoned. After the full-
text reading, studies for inclusion in the review were selected. Of the 8
studies included in the systematic review, we selected 7 that followed
appropriate methods for inclusion in the meta-analysis. One study11
was excluded from the meta-analysis because we were unable to ob-
tain effect measures for the entire cohort of patients.
2.5 | Data extraction
Data were extracted independently by 2 reviewers. The following
data were retrieved from the studies: author names, date of pub-
lication, number of participants, indication for LNG-IUS use, study
design, case and control definitions, outcomes, and risk factors for
breast cancer. In addition, we logged the reported adjusted risk esti-
mates for breast cancer among LNG-IUS users according to the pro-
posed age strata. All data were obtained from the published results
and are summarized in Table 1.
2.6 | Assessment of risk of bias of the included
studies
Two independent reviewers assessed the methodological quality
of the studies using the Downs and Black instrument. This quality
16000412, 2020, 8, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.13817 by Nat Prov Indonesia, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
assessment checklist comprises 27 questions, with a maximum pos-
sible score of 28 points for randomized studies and 25 points for
non-randomized studies. The reviewers assessed the methodo-
logical quality of each study and the risk of bias for the following
domains: reporting bias (10 items), external validity bias (3 items), in-
ternal validity bias (7 items), confounding bias (6 items), and power of
studies (1 item). We gave scores of 0 or 1 for each risk of bias domain
and the associated specific questions, except for one item in report-
ing the subscale for the analysis of the distribution of confounders,
which was scored 0, 1, or 2. Finally, the overall quality of evidence
for each study was rated depending on the final score: excellent (26-
28), good (20-25), fair (15-19), or poor (<14).
2.7 | Statistical analyses
The meta-analysis was performed using the “metagen” library for
the R suite. We derived the effect size of LNG-IUS use on breast
cancer risk directly from the reported effect measures (odds ratio
[OR], relative risk [RR], and standardized incidence ratio [SIR]). We
considered the ratios reported in each individual study and derived
their standard errors from the reported 95% CI. All ratios (OR, RR,
SIR) and their respective 95% CI were obtained from the published
tables for each individual study. As mentioned above, studies were
stratified according to the age of the target population (<50 years,
≥50 years, or mixed). The study by Heikkinen et al12 separately re-
ported on patients of both strata and so appears twice in the meta-
analysis forest plot. We obtained the random-effects estimate of the
RR for breast cancer development after LNG-IUS insertion owing to
high study heterogeneity (I2  =  78%). Funnel plot analysis revealed
no publication bias (funnel plot asymmetry), with P = .635 in Egger’s
test.13
3 | R E S U LT S
We identified 96 studies and manually cross-referenced and ex-
cluded duplicate articles. Seventy articles were excluded after the
application of the inclusion and exclusion criteria, resulting in the as-
sessment of 26 full-text articles. Eight studies were deemed suitable
for inclusion in this review (Figure 1).
Three of the selected papers were case-control studies,12,14,15
whereas 5 were cohort studies.11,16-19 Four of them were conducted
in Finland,11,12,14,16 1 in Germany,15 1 in Denmark,19 1 in Norway,17
and 1 in Israel18 (Table 1).
3.1 | Systematic review of studies addressing LNG-
IUS use and breast cancer risk
Four of the 8 studies in this review reported an increased breast cancer
risk in women using LNG-IUS.12,14,16,19 Taking non-users of LNG-IUS
in the general Finnish female population as the reference for standard
 TA B L E 1   Summary of the studies included

Population ref Adjustment

CONZ et al.

Author Design Objective Methods Population (comparative) variables Results

a
Dinger, 2010 Case-control To assess breast Retrospective study used a Cases: women diagnosed Women using BMI, family history OR for the breast cancer among women
(retrospective) cancer risk non-inferiority design and with breast cancer copper-IUD of breast cancer, who had ever used LNG-IUS vs
of LNG-IUS the null hypothesis to be (in situ or invasive) younger than age at first birth, Copper-IUD (adjusted OR 0.99, 95%
compared to tested was OR ≥1.5. younger than 50 years 50 years of age. age at menarche, CI 0.88-1.12). Among current users of
copper-IUD users old. Controls: nation and physical LNG-IUS vs users of copper-IUD (OR)
in women below populations registry in activity. LNG-IUS = 0.85 (95% CI 0.52-1.39).
the age of 50 years Finland, and in Germany,
old. neighborhood selected
by a controlled random
route method.
Soini, 2015b Cohort To test the Standardized incidence All Finnish women who Breast cancer No adjustment of SIR invasive ductal carcinoma
(retrospective) hypothesis that ratio-SIR (observed- received reimbursement incidence rate their analyses for (IDC) = 1.20 (95% CI 1.14-1.25) and for
risk for lobular to-expected ratio) was for the LNG-IUS among general factors related to lobular carcinoma was SIR (ILC) = 1.33
breast cancer is calculated by dividing purchase prescribed for female population breast cancer risk. (95% CI 1.20-1.46). For more than
elevated among the number of observed treatment or prevention of similar age during 5 years had increased invasive lobular
LNG-IUS users. cancer cases by the of HMB at the age the same time breast cancer risk SIR (ILC) = 1.40 (95%
number of expected of 30-49 years old in period. CI 1.20-1.62), which increased to SIR
cancers. 1994-2007. for ductal carcinoma SIR (IDC) = 1.25
(95% CI 1.16-1.34). The risk of IDC
was significantly higher only in women
using LNG-IUS for more than 10 years
SIR (IDC) = 1.26 (95% CI 1.14-1.38).
Lyytinen, Case-control To evaluate the A multivariate conditional Cases: All Finnish women Women from the Age at the first birth Comparing the 329 women users of
2009c (retrospective) association logistic regression model diagnosed with their first Finnish Population and the parity. LNG-IUS with the 708 controls of the
between was used to estimate invasive breast cancer Register without same age, there was an increased risk
postmenopausal by means of the OR the between 50 and 62 years systemic HT (only for breast cancer in the cases, with
hormone therapy relative risk for breast between 1 January 1995 vaginal estrogens OR = 1.53; 95% CI 1.33-1.75 (P = .001).
(HT) and the cancer associated with and 31 December 2007, were allowed).
risk for breast each category of HT. were identified from the
cancer in recently Finnish Cancer Registry.
postmenopausal Controls: For each cancer
Finnish women. case, 3 control women
born at the same time
and alive and free of
breast cancer at the
date of breast cancer
diagnosis of the case.
|       973

(Continues)

16000412, 2020, 8, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.13817 by Nat Prov Indonesia, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 TA B L E 1   (Continued)
|

Population ref Adjustment

974      

Author Design Objective Methods Population (comparative) variables Results

Backman, Cohort To evaluate breast Epidemiologic study based LNG-IUS users, between Incidence data No adjustment of For women aged 30-34 years incidence
2005d (retrospective) cancer incidence on a questionnaire sent to January 1990 and derived from the their analyses for per 100 000 is 27.2 in LNG-IUS and
in users of the women in Finland who had December 1993, national Finnish factors related to 25.5 in general population (95% CI
LNG-IUS. had a LNG-IUS inserted. of Finnish female Cancer Registry breast cancer risk. P = .84), 35-39 years 74.0 in LRIS vs
The study was based on population (30-54 years from the year 1998. 49.2 (95% CI P = .056), 40-44 years
a reanalysis of the data of age). 120.3 vs 122.4 (95% CI P > .99),
obtained in an earlier post 45-49 years 203.6 vs 232.5 (95% CI
marketing study and the P = .41) and finally for 50-54 years, the
data on breast cancer incidence per 100 000 woman-years
diagnoses from Finnish in LNG-IUS is 258.5 vs 272.6 (95% CI
Cancer Registry from the P = .85) in general population.
year 1998.
Mørch, 2018e Cohort To evaluate breast Nationwide prospective All women living in Women who Age, education, Among women who used the LNG-IUS
(prospective) cancer incidence cohort study involving Denmark who were had never previous OC use, intrauterine system, the relative risk
in users of the all women in Denmark between 15 and 49 years used hormonal endometriosis, of breast cancer was 1.21 (95% CI
LNG-IUS. between 15 and 49 years (a total of 1 837 297 contraception. parity, and 1.11-1.33), compared with never users.
of age. Nationwide women) who had not family history of This risk did not differ significantly
registries provided had cancer or venous premenopausal from the risk associated with products
individually updated thromboembolism and breast or ovarian containing oral levonorgestrel alone.
information about who had not received cancer.
the use of hormonal treatment for infertility
contraception. current and recent
users of hormonal
contraception.
Siegelmann- Cohort To evaluate the A cohort of all Maccabi LNG-IUS users and Women who were Age at the start of After 5 years of study, 16 DCIS and
Danieli, (retrospective) incidence of Healthcare Services age-matched “controls” not exposed to follow up, female 120 invasive tumors were reported
20176 breast cancer in female members aged were selected from other hormone hormones in in LNG-IUS users and in the controls,
perimenopausal 40-50 years between 338 184 women who therapies in the the form of oral these included 42 DCIS and 241
women using 1/2003 and 12/2013 was were 40-50 years old 5 years preceding contraceptives invasive tumors. Five-year Kaplan-
LNG-IUS. used to identify LNG-IUS between January 2003 inclusion and during (OC), fertility Meyer estimates for overall BC risk
users as ‘‘cases,’’ and 2 and December 2013. study period till last drugs, or HT or in LNG-IUS users and controls were
age-matched non-users as Cases included all follow up. prophylactic use of 1.2% (SE 0.1%) and 1.1% (SE 0.06%),
‘‘controls’.’ perimenopausal users tamoxifen. respectively (P = .23). For DCIS risk,
of LNG-IUS in this the respective values were 0.14% (SE
timeframe. The controls 0.03%) and 0.16% (SE 0.03%) (P = .22).
(2 per case) were
selected sequentially
to be aged-matched
±2 years.
CONZ et al.

(Continues)

16000412, 2020, 8, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.13817 by Nat Prov Indonesia, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 TA B L E 1   (Continued)
CONZ et al.

Population ref Adjustment

Author Design Objective Methods Population (comparative) variables Results

Heikkinen, Case-control To estimate the Breast cancer cases Cases: women diagnosed Never users of Birth year, A statistically significant increase
2015f (retrospective) association from Finland in 2009 with breast cancer any hormonal previous hormone in breast cancer risk was observed
between use matched population (in situ or invasive) at contraceptive contraceptive use for postmenopausal women with
of exogenous controls. Conditional 22-60 years of age (exclusively copper and HT, age at exclusive use of LNG-IUS (use before
hormones and logistic regression was between 1 January 2000 intrauterine device). menarche, parity, breast cancer diagnosis) an odds
breast cancer risk. used to estimate odds and 31 December 2007 family history of ratio of 1.48 (95% CI 1.10-1.99) was
ratios and their 95% CI. from the Finnish Cancer breast cancer, BMI, observed in postmenopausal women.
For validation, exposure Registry. years of schooling,
prevalences were Controls: were retrieved smoking, and
compared with population from the central alcohol use.
data from Statistics population register by
Finland and two large a third party under a
population-based surveys. delivery agreement.
Jareid, 2017g Cohort To investigate 104 318 women from the Women from the Never users of Age at the start of Median age at inclusion was 52 years
(prospective) the association Norwegian Women and Norwegian Women and LNG-IUS. follow up, BMI, and mean follow-up time was 12.5
between hormone Cancer Study. Exposure Cancer Study, 9144 of physical activity (standard deviation 3.7) years, for
use and hormone- information was taken whom were ever users of level at enrolment, a total of 1 305 435 person-years.
dependent female from self-administered LNG-IUD and 95 174 of maternal history of Among ever users of LNG-IUS there
cancers. questionnaires, and whom were never users breast cancer, age were 297 cases of breast cancer.
cancer cases were of LNG-IUS. at menarche, ever Whenever users were compared
identified through linkage use of OCs, parity to never users of LNG-IUS, the
to the Cancer Registry of and menopausal multivariable RR of breast cancer was
Norway. status at the start 1.03 (0.91, 1.17).
of follow up.
a
Dinger J, Bardenheuer K, Minh TD, Soini T, Hurskainen R, Grénman S, et al. Levonorgestrel-releasing and copper intrauterine devices and the risk of breast cancer. Contraception 2010.
b
Soini T, Hurskainen R, Grénman S, Mäenpää J, Paavonen J, Joensuu H, et al. Levonorgestrel-releasing intrauterine system and the risk of breast cancer: a nationwide cohort study. Acta Oncol 2016.
c
Lyytinen HK, Dyba T, Ylikorkala O, Pukkala EI. A case-control study on hormone therapy as a risk factor for breast cancer in Finland: intrauterine system carries a risk as well. Int J Cancer 2010.
d
Backman T, Rauramo I, Jaakkola K et al. Use of the levonorgestrel-releasing intrauterine system and breast cancer. Obstet Gynecol 2005.
e
Mørch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard Ø. Contemporary hormonal contraception and the risk of breast cancer. N Engl J Med 2017.
f
Heikkinen S, Koskenvuo M, Malila N, Sarkeala T, Pukkala E, Pitkäniemi J. Use of exogenous hormones and the risk of breast cancer: results from self-reported survey data with validity assessment. Cancer
Causes Control. 2016.
g
Jareid M, Thalabard JC, Aarflot M, Bøvelstad HM, Lund E, Braaten T. Levonorgestrel-releasing intrauterine system use is associated with a decreased risk of ovarian and endometrial cancer without
increased risk of breast cancer. Results from the NOWAC study. Gynecologic Oncol. 2018.
h6
Siegelmann-Danieli N, Katzir I, Landes JV, Segal Y, Bachar R, Rabinovich HR, et al. Does levonorgestrel-releasing intrauterine system increase breast cancer risk in peri-menopausal women? An HMO
perspective. Breast Cancer Res Treat 2018.
|       975

16000412, 2020, 8, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.13817 by Nat Prov Indonesia, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
 |

16000412, 2020, 8, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.13817 by Nat Prov Indonesia, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
976       CONZ et al.

Identification
Records identified through database Additional records identified
searching through other sources
(n = 94) (n = 2)

Records after duplicates removed

(n = 70)
Records excluded
Screening

(n = 17)
10 articles: women
Records screened with breast cancer
(n = 26)
7 articles: women
with high risk for
breast cancer
Full-text articles assessed
Eligibility

for eligibility
(n =9)

Elingjord-Dale et al. [1]

Backman et al. study excluded because
Studies included in the
[2] study was not the authors did not
Systematic Review
included in the (n = 8) differentiate types of
meta-analysis due IUD (Cu or LNG).
to a lack of direct
Included

patient data. Studies included in the

meta-analysis
(n = 7)

F I G U R E 1   PRISMA flowchart

breast cancer risk (for comparison against LNG-IUS users), Soini et al16
described 2015 new breast cancer cases in women aged 30-49 years
using LNG-IUS for heavy menstrual bleeding (1598 invasive ductal
carcinoma, 376 lobular carcinoma, and 41 carcinoma of other histo-
logical types) during a mean follow up of 11 years (maximum 19 years).
The SIR for invasive ductal carcinoma was 1.20 (95% CI 1.14-1.25,
P < .001), whereas that for invasive lobular carcinoma was 1.33 (95%
CI 1.20-1.46, P < .001). However, the authors of that study found that
only women who used LNG-IUS for >5 years had an increased risk for
invasive lobular breast cancer (SIR = 1.40, 95% CI 1.20-1.62, P < .001).
Lyytinen et al14 evaluated the risk of breast cancer in post-
menopausal women aged 50-62  years using LNG-IUS for endo-
metrial protection. These women were compared against women
who had never used hormonal therapy (HT) or had not used HT
for at least the last 6 months. In this study, several drug regimens
for HT were analyzed, including oral agents, injectable drugs, and
LNG-IUS; however, only 14% of the women used LNG-IUS exclu-
sively for endometrial protection. Comparing LNG-IUS users with
controls matched for age, the authors observed an increased risk
of breast cancer in LNG-IUS users, with an OR of 1.53 (95% CI
1.33-1.75, P = .001).
A similar case-control study by Heikkinen et al12 reported data
from the Finnish Cancer Registry. A total of 13  265 breast cancer
cases were identified. The median age for both cases and controls
was 57.5 years. In that study, the breast cancer risk among LNG-IUS
users was compared with the overall breast cancer risk for the gen-
eral female Finnish population (premenopausal or postmenopausal).
The authors detected a positive association between breast cancer
risk and use of LNG-IUS in postmenopausal women (OR  =  1.48,
95% CI 1.10-1.99). There was no increased breast cancer risk in pre-
menopausal women using LNG-IUS in that study (OR = 0.77, 95% CI
0.52-1.13).
Mørch et al19 published a study based on data from 1.8 million
Danish women who were followed up for an average of 10.9 years.
Women who used LNG-IUS at the time of data collection (current
users) or who reported recent use of contraception had a higher risk
of breast cancer than women who had never used hormonal contra-
ceptives. Data from 503 441 women-years using LNG-IUS showed
an RR of 1.21 (95% CI 1.11-1.33). Mørch et al19 reported 571 cases
of breast cancer among LNG-IUS users.
Backman et al11 performed a re-analysis of the data obtained
in an earlier postmarketing study about the adverse effects of a
commercial LNG-IUS for contraception. The incidence of breast
cancer in LNG-IUS users by age group per 100 000 women-years
was contrasted with the breast cancer incidence data derived from
the National Finnish Cancer Registry. For three age groups (40-
44, 45-49, and 50-54 years), the point estimates for breast cancer
incidence were higher in the average population than in LNG-IUS

CONZ et al.
users. In two age groups (30-34 and 35-39 years), the point esti-
mate in LNG-IUS users was higher than that in the average Finnish
female population. However, these trends were not significant
considering 95% CI.
With respect to case-control studies, Dinger et al15 evaluated
the risk for breast cancer in users of LNG-IUS vs that in users
of a copper intrauterine device (Cu-IUD), using population-based
data from Germany and Finland. Devices, either LNG-IUS or Cu-
IUD, were used for contraception by women up to age 50 years.
Data were retrieved from Finnish and German cancer registries.
Data from 5133 breast cancer cases and 20 452 non-breast can-
cer cases were included. The point estimate of the crude and
adjusted ORs for the risk of breast cancer among women who
had ever used LNG-IUS compared with those who had ever used
Cu-IUD was OR LNG-IUS = 1.04 (95% CI 0.93-1.17). The adjusted
OR was 0.88 (95% CI 0.49-1.59) among current LNG-IUS users
(women who were using an IUD at the time of breast cancer
diagnosis).
Siegelmann-Danieli et al18 performed a retrospective cohort
study in perimenopausal women aged 40-50 years from Israel,18 in
which the breast cancer risk was compared between 13 354 LNG-
IUS users and 27 324 age-matched non-users of LNG-IUS. Patients
receiving hormone replacement therapy or oral contraceptive (OCs)
were excluded from the analysis. No significant differences in the
5-year Kaplan-Meier estimates for overall breast cancer were ob-
served; however, there was a trend towards a higher risk for breast
cancer in LNG-IUS users than in non-users (5-year Kaplan-Meier es-
timate: 1.06% vs 0.93%, P = .051). This difference was primarily ob-
served in younger women (40-45 years; 0.88% vs 0.69%, P = .014),
whereas it was non-significant (1.44% vs 1.21%, P  =  .26) in older
women (46-50 years).
A Norwegian-based prospective cohort study (NOWAC—
Norwegian Women and Cancer study)17 logged data from 9144
LNG-IUS users and 95 174 non-users. After 12.5 years, 297 breast
cancer cases were reported. The RR of breast cancer in LNG-IUS
users was 1.03 (95% CI 0.91-1.17) and body mass index (BMI), physi-
cal activity level, maternal history of breast cancer, and menopausal
status were considered in the analyses.
3.2 | Meta-analysis
Seven of the 8 studies reviewed had complete data on the number
of users and non-users of LNG-IUS and the risk of breast cancer
after LNG-IUS insertion. Three12,14,15 were case-control studies and
16-19 11
4 were cohort studies (Figure 2). The study by Backman et al
was not included in the meta-analysis owing to a lack of direct pa-
tient data, as the effects of LNG-IUS use were reported for 5-year
age strata of women. We failed to reach the authors to obtain usable
effect measures.
A funnel plot (Figure 3) was generated, and a linear regression
test of funnel plot asymmetry was performed to assess publication
bias. Funnel plot symmetry and a negative result from the funnel
|
16000412, 2020, 8, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.13817 by Nat Prov Indonesia, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
      977
F I G U R E 2   Forest Plot meta-analysis
plot asymmetry test (Egger’s test, P = .635)13 led us to conclude that
there is no detectable publication bias.
Our meta-analysis model was constructed using data derived
from the original results reported in the studies. We stratified the
analyses by the age strata of the women included in each paper
(<50  years, ≥50  years, and mixed). Because of study heterogene-
ity (I2 = 78%), especially among studies reporting on patients aged
<50  years, we used the random-effects model. By standardizing
the effect sizes of all studies and combining the results from these
7 studies, the meta-analysis indicated an increased breast cancer
risk in LNG-IUS users: age <50 years, OR = 1.12 (95% CI 1.02-1.22,
I2  =  66%, P  =  .02); age ≥50  years, OR  =  1.52 (95% CI 1.34-1.72,
I2  =  0%, P  =  .84). For all women, the meta-analysis indicated an
increased breast cancer risk in LNG-IUS users (OR  =  1.16, 95% CI
1.06-1.28, I2 = 78%, P < .01).
3.3 | Controlling for known breast cancer
risk factors
The control of factors influencing the breast cancer incidence (educa-
tion, socioeconomic status, reproductive and hormone factors, pre-
vious history of breast cancer, use of alcohol, elevated BMI)20 varied
greatly among the studies included in this meta-analysis. Backman et
al11 and Soini et al16 did not adjust their analyses for factors related
to breast cancer risk. Siegelmann-Danieli et al18 excluded from the
analysis women with exposure to female hormones in the form of
OCs, fertility drugs, or HT or prophylactic use of tamoxifen in the
5 years preceding day 1 and through November 2015. Dinger et al15
considered potential risk factors for breast cancer, including BMI,
family history of breast cancer, age at first birth, age at menarche,
and physical activity. Heikkinen et al12 adjusted the results for year
of birth, previous hormonal contraceptive use and HT, age at me-
narche, parity, family history of breast cancer, BMI, years of school-
ing, smoking, and alcohol use. Lyytinen et al14 were able to control
only for age at first birth and parity. Jareid et al17 identified age at the
start of follow up, BMI, physical activity level at enrolment, maternal
 |
978       CONZ et al.
F I G U R E 3   Funnel plot of the studies included
history of breast cancer, age at menarche, ever use of OCs, parity,
and menopausal status at the start of follow-up. Mørch et al19 ad-
justed for age, education, previous OC use, endometriosis, parity,
and family history of premenopausal breast or ovarian cancer.
3.4 | Use of OCs and postmenopausal HT before
LNG-IUS insertion
The authors of the studies included in the meta-analysis had differ-
ent approaches to data from OC and HT use before the insertion
18
of LNG-IUS. Siegelmann-Danieli et al excluded from the analysis
women with exposure to female hormones in the form of OCs, fer-
tility drugs, or HT or prophylactic use of tamoxifen in the 5 years
15
preceding day 1 and through November 2015. Dinger et al cap-
tured information about hormone exposure (contraception, HT)
and controlled this information as a confounding factor; however,
there was no information about the duration of previous use and
when/if it was withdrawn. Heikkinen et al12 categorized the dura-
tion of hormonal contraceptive use as none, 1 month, 1-6 months,
6 months to 2 years, 2-4 years, 4-8 years, 8-12 years, 12-16 years,
16-20 years, 20-25 years, and 25 years. They pooled these catego-
ries to form a trinomial variable, with levels of 1 month, 1-6 months,
and 6  months to 2  years. Thereafter, these women were further
grouped according to the duration of exposure to HT (<2 or
>2  years). Use of IUD was categorized as ever use vs never use.
16000412, 2020, 8, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.13817 by Nat Prov Indonesia, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
For ever users, the type of device was also asked, with the options
being Cu-IUD, hormone-releasing IUD, and other IUDs. For further
analysis, a reference category with never users of any hormonal
contraceptive (hormone-releasing IUD or other hormonal contra-
ceptives) was also formed. The use of HT was classified as ever use
vs never use regardless of duration. Information on current use of
HT was used only as a reference factor in survey validation. Jareid
et al17 included OC use as a dichotomous variable and analyzed OC
use by duration; however, they did not change the estimate of the
main exposure and did not adjust for time since OC use. Mørch et
al19 categorized OC use as current use or recent use (discontinua-
tion within the previous 6  months) or previous use (discontinua-
tion >6 months previously). LNG-IUS was assumed to be used for
4 years, unless the woman became pregnant or another hormonal
contraceptive was prescribed before the end of the 4-year period.
Backman et al,11 Lyytinen et al,14 and Soini et al16 did not control
for previous OC use.
3.5 | Methodological quality of the studies
The methodological quality of the studies was evaluated using the
Downs and Black instrument for adapted quality assessment. 21 Five
studies12,15-17,19 were considered to be “good”, whereas the three re-
maining studies were considered “fair”.11,14,18 Table 2 lists the risk of
bias of each of the selected studies.
 |

16000412, 2020, 8, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.13817 by Nat Prov Indonesia, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CONZ et al.       979

TA B L E 2   Methodological quality of the studies using the Downs and Black Instrument adapted quality assessment checklist

Studies Dinger Soini Lyytinen Backman Mørch Siegelmann Heikkinen Jareid

Year of publication 2010a 2015b 2009c 2005d 2018e 2017f 2015g 2017h

Reporting
Is the hypothesis/aim/objective of the study clearly 1 1 1 1 1 1 1 1
described?
Are the main outcomes to be measured clearly described in 1 1 1 1 1 1 1 1
the Introduction or Methods section?
Are the characteristics of the patients included in the study 1 1 1 1 1 1 1 1
clearly described?
Are the interventions of interest clearly described? 1 1 1 1 1 1 1 1
Are the distributions of principal confounders in each 2 0 1 0 1 0 1 2
group of participants to be compared clearly described?
Are the main findings of the study clearly described? 1 1 1 1 1 1 1 1
Does the study provide estimates of the random variability 1 1 1 1 1 1 1 1
in the data for the main outcomes?
Have all important adverse events that may be a 0 0 0 0 0 0 0 0
consequence of the intervention been reported?
Have the characteristics of patients lost to follow up been 1 1 0 1 0 0 0 0
described?
Have actual probability values been reported for the main 1 1 1 1 1 1 1 1
outcomes except where the probability value is <.001?
External validity
Were the women asked to participate in the study 0 1 0 0 1 0 0 0
representative of the entire population from which they
were recruited?
Were those women who were prepared to participate 1 1 1 1 1 1 1 1
representative of the entire population from which they
were recruited?
Were the stay, places, and facilities where the patients 1 1 1 1 1 1 1 1
were treated, representative of the treatment the
majority of patients receive?
Internal validity—bias
Was an attempt made to blind study participants to the 0 0 0 0 0 0 0 0
intervention they have received?
Was an attempt made to blind those measuring the main 0 0 0 0 0 0 0 0
outcomes of the intervention?
If any of the results of the study were based on “data 1 1 1 1 1 1 1 1
dredging”, was this made clear?
In trials and cohort studies, do the analyses adjust 1 1 1 1 1 1 1 1
for different lengths of follow up of patients, or in
case-control studies, is the time period between the
intervention and outcome the same for cases and
controls?
Were the statistical tests used to assess the main 1 1 1 1 1 1 1 1
outcomes appropriate?
Was compliance with the intervention/s reliable? 1 1 1 1 1 1 1 1
Were the main outcome measures used accurate (valid and 1 1 1 1 1 1 1 1
reliable)?
Internal validity—confounding (selection bias)                
Were the patients in different intervention groups (trials 0 1 1 1 1 1 1 1
and cohort studies) or were the cases and controls (case-
control studies) recruited from the same population?

(Continues)
 |

16000412, 2020, 8, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.13817 by Nat Prov Indonesia, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
980       CONZ et al.

TA B L E 2   (Continued)

Studies Dinger Soini Lyytinen Backman Mørch Siegelmann Heikkinen Jareid

Year of publication 2010a 2015b 2009c 2005d 2018e 2017f 2015g 2017h

Were study participants in different intervention groups 1 1 1 1 1 1 1 1

(trials and cohort studies) or were the cases and controls
(case-control studies) recruited over the same period of
time?
Were study participants randomized to intervention 0 0 0 0 0 0 0 0
groups?
Was the randomized intervention assignment concealed 0 0 0 0 0 0 0 0
from both patients and health care staff until recruitment
was complete and irrevocable?
Was there adequate adjustment for confounding in the 1 0 1 0 1 1 1 1
analyses from which the main findings were drawn?
Were losses of patients to follow up taken into account? 1 1 0 0 1 0 1 1
Power
Did the study have sufficient power to detect a clinically 1 1 1 1 1 1 1 1
important effect where the probability value for a
difference being due to chance is less than 5%?
Final score 21 20 19 18 21 18 20 21
a
Dinger J, Bardenheuer K, Minh TD, Soini T, Hurskainen R, Grénman S, et al. Levonorgestrel-releasing and copper intrauterine devices and the risk of
breast cancer. Contraception [Internet]. 2011;83(3):211-17. Available from: http://dx.doi.org/10.1016/j.contr​acept​ion.2010.11.009
b
Soini T, Hurskainen R, Grénman S, Mäenpää J, Paavonen J, Joensuu H, et al. Levonorgestrel-releasing intrauterine system and the risk of breast
cancer: A nationwide cohort study. Acta Oncol [Internet]. 2016;55(2):188-92. Available from: http://www.ncbi.nlm.nih.gov/pubme​d/26243443
c
Lyytinen HK, Dyba T, Ylikorkala O, Pukkala EI. A case-control study on hormone therapy as a risk factor for breast cancer in Finland: Intrauterine
system carries a risk as well. Int J Cancer [Internet]. 2010 Jan 15 [cited 2016 Aug 29];126(2):483-9. Available from: http://www.ncbi.nlm.nih.gov/
pubme​d/19588504
d
Backman T, Rauramo I, Jaakkola K et al. Use of the levonorgestrel-releasing intrauterine system and breast cancer. Obstet Gynecol [Internet].
2005;106:813- Available from: http://linki​nghub.elsev​ier.com/retri​eve/pii/S0015​02820​7012009
e
Mørch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard Ø. Contemporary hormonal contraception and the risk of breast cancer. N
Engl J Med [Internet]. 2017;377(23):2228-39. Available from: http://www.nejm.org/doi/10.1056/NEJMo​a1700732
f
Siegelmann-Danieli N, Katzir I, Landes JV, Segal Y, Bachar R, Rabinovich HR, et al. Does levonorgestrel-releasing intrauterine system increase breast
cancer risk in peri-menopausal women? An HMO perspective. Breast Cancer Res Treat 2018;167(1):257-62.
g
Heikkinen S, Koskenvuo M, Malila N, Sarkeala T, Pukkala E, Pitkäniemi J. Use of exogenous hormones and the risk of breast cancer: results from self-
reported survey data with validity assessment. Cancer Causes Control 2016;27(2):249-58.
h
Jareid M, Thalabard JC, Aarflot M, Bøvelstad HM, Lund E, Braaten T. Levonorgestrel-releasing intrauterine system use is associated with a
decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer. Results from the NOWAC Study. Gynecol Oncol 2018:4-9.

4 |  D I S CU S S I O N examined in 212,14 of the 8 studies11,12,14-19 included in this review,

This systematic review and meta-analysis points towards an aug-
mented breast cancer risk among LNG-IUS users, especially for
women aged 50  years or older. Importantly, there are no rand-
omized data for women using LNG-IUS vs those using other meth-
ods. In addition, the studies in this meta-analysis included cohorts
of women using LNG-IUS for different reasons, including contra-
ception, abnormal bleeding, endometrial protection, and other
medical reasons.
We obtained separate risk estimates for women according to
different age strata, which allowed us to perform a stratified me-
ta-analysis. The meta-analysis clearly demonstrated that the breast
cancer risk increases in parallel with the age strata of LNG-IUS users.
In fact, in the meta-analysis, only 2 of 5 studies reporting on women
aged <50  years found an increased risk for breast cancer among
LNG-IUS users.16,19 The breast cancer risk in older women was
and both studies indicated that older (in general, postmenopausal)
women using LNG-IUS for reasons other than contraception have a
higher breast cancer risk.12,14
Nonetheless, we were particularly concerned about the re-
ported and unreported use of LNG-IUS after a period of expo-
sure to other forms of hormonal contraception, typically combined
OCs.19 Hence, if there is no or only a very small gap between pre-
vious hormonal contraceptive use and insertion of an IUS, then
it will be difficult to discriminate the possible biological effects
of LNG-IUS itself from a lingering effect of previous hormonal
contraception. Most authors acknowledge that “Insufficient
adjustment for this (OC/HT use) and for use of other hormonal
contraceptives may have caused residual confounding in our esti-
mates.”14,16 Notably, it is worth mentioning that some studies in-
cluded in the meta-analysis had no results adjusted for OC use (yes
or no, although duration was not accounted for) before LNG-IUS

CONZ et al.
insertion. The study by Mørch et al,19 however, must be singled
out as the only study to have found evidence of an increased
breast cancer risk in women who had used LNG-IUS for >10 years,
a group of women for whom the risk attributable to previous use
of other hormonal contraception methods or HT is offset by the
time elapsed since these other treatments had been terminated.
It is important to note that some risk factors for breast can-
cer may be relatively common in women with clinical indications
for perimenopausal/postmenopausal LNG-IUS use. Abnormal
bleeding and heavy menstrual bleeding are indications for the use
of LNG-IUS, 22 and these conditions are more frequent in obese
women who are at increased risk of breast cancer owing to long
periods of anovulation or abnormal ovulation. 23 Other factors of
similar association are hypoestrogenic conditions and premature
ovarian failure. 23,24
Postmenopausal HT has also been associated with breast can-
cer, making it difficult to discriminate the possible biological ef-
fects of IUS in protecting the uterus in postmenopausal women
from the effects of concurrent use of HT. 25 Thereby, Jones et al, 23
in a cohort of 113 693 English women older than 16 years, eval-
uated the risks associated with HT for the development of breast
cancer. These authors controlled for the aforementioned factors.
The hazard ratio for invasive and in situ breast cancer, adjusted
for age at menopause, was 1.95 (95% CI 1.55-2.46, P  =  .001) for
current users of all types of HT compared with women who had
never used HT. The risk increased by 3.8% per year (95% CI 0.4-
7.3%, P = .027) of HT use, and HT use in excess of 15 years was
associated with a hazard ratio of 2.02 (95% CI 1.12-3.66, P = .020).
More recently, a large meta-analysis concluded that in women of
average weight in developed countries, 5  years of HT (estrogen
plus daily progestogen) starting at age 50 years could result in one
case of breast cancer per 50 HT users. The HT-attributable breast
cancer risk decreases to one case in every 70 users of estrogen
plus intermittent progestogen, and one in every 200 users of es-
trogen only. 26
It can be argued that the question of whether LNG-IUS use is safe
from the oncological standpoint remains unresolved, largely owing
to unsurmountable difficulties in discriminating the effects of several
confounding factors in the analysis of data obtained from LNG-IUS
users. From a strictly technical point of view, that affirmation is true,
as there are no randomized studies on the association between LNG-
IUS use and breast cancer. However, our meta-analysis of non-ran-
domized cohorts showed a clear association between LNG-IUS use
and breast cancer risk, which seems strikingly pervasive among users
aged ≥50 years. This risk was observable in studies examining women
with different clinical and epidemiological backgrounds.
In our opinion, the increased risk of breast cancer among LNG-
IUS users needs to be weighed against the potential health benefits
of LNG-IUS, such as highly effective, long-acting, and reversible con-
traception. LNG-IUS has many proven useful applications, being, for
example, an effective contraception method, and effective to treat
heavy menstrual bleeding. However, caution is needed when indi-
cating LNG-IUS for long periods of use, especially in women with
|
16000412, 2020, 8, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.13817 by Nat Prov Indonesia, Wiley Online Library on [20/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
      981
other known breast cancer risk factors such as older age, obesity,
and familial predisposition.
5 | CO N C LU S I O N
We obtained evidence suggesting a link between breast cancer
risk and LNG-IUS use at any age and for any indication. However,
methodological issues across the available studies may cast some
doubts about this relation, and concerns about problems inherent
to studying such a complex issue in different sets of women are
certainly worth considering. If our analysis is valid, the attributable
breast cancer risk is most likely marginal for premenopausal LNG-
IUS users; however, for women older than 50 years, there may be a
nearly 40% increased breast cancer risk. Given the evidence show-
ing an association between hormonal contraception and HT with
breast cancer risk, it is difficult to believe that LNG-IUS use may be
devoid of any oncological risk. Users of LNG-IUS should therefore
be aware of these trends, and risks associated with LNG-IUS use
must be balanced against its proven health benefits, eg effective
treatment of heavy menstrual bleeding and reduced need for surgi-
cal interventions.
C O N FL I C T O F I N T E R E S T
Luis Bahamondes received an honorarium from Bayer to be a mem-
ber of the advisory board. The other authors have no conflicts of
interest to disclose.
ORCID
Livia Conz  https://orcid.org/0000-0002-8277-3554
Bruna Salani Mota  https://orcid.org/0000-0001-9567-1066
Luis Bahamondes  https://orcid.org/0000-0002-7356-8428
Maíra Teixeira Dória  https://orcid.org/0000-0002-8671-2863
Sophie Françoise Mauricette Derchain  https://orcid.
org/0000-0003-1029-9993
Rachel Rieira  https://orcid.org/0000-0002-9522-1871
Luis Otavio Sarian  https://orcid.org/0000-0002-9554-6131
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How to cite this article: Conz L, Mota BS, Bahamondes L,
et al. Levonorgestrel-releasing intrauterine system and breast
cancer risk: A systematic review and meta-analysis.
Acta Obstet Gynecol Scand. 2020;99:970–982.
https​://doi.org/10.1111/aogs.13817​