Antes de dar anticonceptivos, es necesario hacer el uso de la

historia clínica, interrogar a la paciente para verificar los

factores de riesgo que tenemos con cada una de ellas.

Los criterios de elegibilidad de la OMS nos indican cuáles son las

contraindicaciones para su uso, aunque la gran mayoría de las pacientes no las
tienen.

Reducir riesgos y morbilidades

El hecho de que una paciente tenga un riesgo para el uso de un anticonceptivo,
pero también tenga el beneficio, debe de ser un reto para el médico al utilizarlo
y tratar de disminuir la reducción del riesgo, es decir, buscar siempre el beneficio
de la paciente.

Características de los anticonceptivos

Todos los hormonales combinados tienen estrógenos y progesterona. Los
estrógenos pueden ser el estradiol o etinilestradiol, en gramaje de 20, 30 y 15
microgramos. Existían dosis más altas que ya no se encuentra en el mercado
porque aumentan el riesgo cardiovascular. Todos los anticonceptivos que están
entre 20 y 30 microgramos son muy seguros.

Elección del anticonceptivo

La manera de elegir un anticonceptivo solo o combinado, ya sea para una
cuestión anticonceptiva u otra condición, tiene que ver con la progestina, ya que
hay progestinas que tienen efecto androgénico, antiandrogénico,
antimineralocorticoide o glucocorticoides, por lo que es el elemento principal
del anticonceptivo porque va a generar el efecto anovulatorio. Por esta razón,
no hay anticonceptivos solamente de estrógenos.

Los estrógenos combinados con progestinas es la manera más fisiología de

anticoncepción o un tratamiento para otra patología, o de progestágenos que
pueden generar más efectos secundarios en la paciente.

Clasificación de las progestinas

Las progestinas provienen del colesterol y unas son de derivadas de la alfa
hidroxi progesterona, otras derivan de la norprogesterona o de la
nortestosterona.

También se pueden clasificar por la manera en que fueron saliendo al mercado.

Primera, segunda, tercera o cuarta generación. Los de primera generación no
son peores o mejores que los de cuarta, todas tienen un beneficio.
Hablando de anovulatorios, levonorgestrel es la progestina más utilizada,
aunque no tiene un efecto antiandrogénico, por lo que no tiene un efecto
adicional como en la piel, cuando buscamos una doble partida para el
tratamiento de nuestras pacientes. La ciproterona tiene un efecto
antiandrogénico, por ejemplo en el síndrome de ovario poliquístico (SOP), o en
las pacientes cuando suben de peso o las que tienen hipotiroidismo y que
simulan un ovario poliquístico. La drospiredona tiene un efecto
antimineralocorticoide, lo que evita la retención de líquidos.

Una de las preguntas frecuentes es “¿voy a subir de peso?”. Sí, si no se cuidan.

No, si se lleva una dieta o se quitan los factores de riesgo, porque lo que genera
el aumento de peso es el estilo de vida, su régimen alimenticio muy
determinado.

La drospirenona tiene buenos efectos a nivel de andrógenos ováricos, por lo

tanto, es una buena elección para ciertos casos de SOP. El dienogest es una de
las mejores progestinas, principalmente para pacientes con dolor pélvico
crónico, endometriosis, dismenorrea, síndrome disfórico premenstrual, por lo
que es una muy buena alternativa para procesos inflamatorios, ya sea
adenomiosis, adenomatosis o endometriosis.

La clormadinona es una de las progestinas más antigua y más utilizada, con poco
efecto antiandrogénico. Por lo que hay que buscar los beneficios fisiológicos,
preventivos o terapéuticos adicionales de los anticonceptivos.

Es importante un buen interrogatorio para determinar las características del

ciclo menstrual. La duración del sangrado tiene que ser de 3 a 7 días, con un
volumen de 5 a 80 ml y una frecuencia de 24 a 35 días más menos 1, por lo que si
se sale de estos parámetros, la paciente amerita tratamiento con un
anticonceptivo, ya que de manera fisiológica, todos pueden regular el ciclo
menstrual. Además se puede regular el aumento del sangrado, que puede
generar anemia, que es lo más frecuente a nivel mundial y más en las mujeres
en etapa reproductiva, por la pérdida mes con mes.

La dismenorrea es otro padecimiento común que puede ser tratado. Esta puede
ser primaria o secundaria. La primaria se presenta cuando la paciente comienza
a menstruar y no hay otra patología. Por lo que si presenta dolor suficiente para
cambiar su estilo de vida, tomar analgésicos o disminuir sus actividades
cotidianas, es necesario el tratamiento. El interrogatorio nos dirá si sí es
candidata a los anticonceptivos hormonales combinados, incluso si la paciente
es adolescente, tiene que recibir tratamiento una vez que se inicia la menarquia,
que no es sinónimo de pubertad precoz o pubertad retardada, donde se tiene
que redireccionar al endocrinólogo o biólogo a la reproducción. Pero si no tiene
estas condiciones y tiene el peso y talla correspondiente a la etapa cronológica,
hay que darlo tratamiento.
Las pacientes que están en etapa perimenopáusica entre los 38 a 48 años, es
normal que tengan una disfunción anovulatoria con o sin síntomas vasomotores
o síntomas que asemejan al climaterio, se pueden beneficiar de ciertas dosis de
anticonceptivos según sus factores de riesgo.

Los anticonceptivos mejoran la densidad mineral ósea, sobre todo en las jóvenes
en que tienen disfunción parcial, no como para diagnosticar menopausia precoz
o temprana, pero que sí necesiten sustitución hormonal. Las mujeres con riesgo
de osteopenia se ven beneficiadas, sobre todo aquellas con un índice de masa
corporal muy bajo o tratamientos crónicos con corticoesteroides, metotrexato
o hipotiroidismo. Todo esto puede ser que beneficie a la paciente. La mejoría de
la masa ósea en general es muy buena.

Los trastornos menstruales se hacen comunes después de los 40 años con

sangrados abundantes, los que se van a abolir con el uso de los hormonales
combinados. Es importante recordar que no es terapia de reemplazo hormonal
porque las dosis son diferentes.

Por lo que la anticoncepción en una mujer entre 40 y 45 años tendrá beneficios

solo si se utilizan hormonales combinados.

Los anticonceptivos también nos ayudan a prevenir patologías. Cuando

estamos hablando de sangrado uterino normal, generado por pólipos, miomas,
adenomiosis o alteraciones en el endometrio o cuestiones funcionales, la
primera línea de tratamiento son los anticonceptivos combinados. En la
miomatosis uterina son la primera línea de tratamiento, porque necesitamos
regular y contrarregular los receptores monoclonales que tienen estos miomas,
aunque no va a disminuir el tamaño del mioma ni la probabilidad de sangrado
por miomas submucosos. De manera inicial daremos hormonales a dosis
normales o a dosis dobles durante 7 o 14 días para saturar los receptores y
muchas veces disminuye el sangrado. Por los que los hormonales combinados
pueden regular los ciclos, disminuir la cantidad de endometrio, el sangrado y el
30 al 40% serán asintomáticos, según la edad y la localización del mioma. Si el
mioma es intramural o cavitario, el tratamiento es quirúrgico, pero se pueden
utilizar para mitigar los síntomas descritos.

En la endometriosis, los hormonales combinados no están contraindicados. Al

contrario, en una endometriosis leve o moderada o posterior una cirugía de un
endometrioma, se debe de dar tratamiento, ya que si no se hace, en 6 meses, un
año o 18 meses va a recidivar. Es importante tener en mente que los hormonales
combinados van a limitar la ovulación, ya que van a evitar que los niveles de
estrógenos se eleven, lo que evita la posibilidad de que estos generan el proceso
inflamatorio o la enfermedad.

Las progestinas son un tratamiento muy adecuado en endometriosis moderada

o severa o en endometriomas, pero pueden generar bochornos y resequedad
vaginal. Los análogos de la GnRH no se usan por más de seis meses, ya que
tienen efectos deletéreos para la densidad mineral ósea o la descalcificación y
generan bochornos. En el tratamiento de la endometriosis, cuando la paciente
no tolera la terapia con análogos de la GnRH, se le puede dar hormonales
combinados de manera más fisiológica, sobre todo en pacientes jóvenes. Por lo
que es importante considerarlos como primera línea para largo plazo, sobre todo
para pacientes que han tenido largos tratamientos con análogos como danazol
o progestinas y que ya no los toleran y que requieren su restitución de
estrógenos.

En el SOP, el dato pivote principal es el aumento de los estrógenos y los

andrógenos. Por lo que hay que verificar el fenotipo, para identificar dónde se
está generando la secreción anómala de andrógenos, que pueden ser los
ovarios, las suprarrenales y de manera periférica. Si el SOP es por secreción
anómala de andrógenos a nivel ovárico, se debe suprimir el funcionamiento, y la
mejor manera son con anticonceptivos combinados. Por lo que si el SOP es de
origen periférico u ovárico, los hormonales combinados son una buena opción.

El engrosamiento endometrial ya sea por SOP, obesidad o por uso de

suplementos, puede terminar en hiperplasia y esta, en cáncer de endometrio.
Por lo que hay que definir los factores de riesgo, determinar si el endometrio
está hipertrófico y posteriormente se hace hiperplásico, a ese se le indica
tratamiento. Los hormonales combinados son una alternativa porque van a
descamar el endometrio. Por ello, para hacer el diagnóstico necesitamos una
biopsia. Se puede omitir la biopsia dependiendo del caso y los factores de riesgo.
Por tanto, los hormonales combinados nos ayudan a disminuir la posibilidad a
largo plazo de cáncer ginecológico.

Una de las restricciones para el uso de anticonceptivos hormonales es el riesgo

de cáncer de mama, pero en las mujeres que no tiene este factor de riesgo, no
se incrementa su riesgo de padecer este tipo de cáncer. Con respecto a las
progestinas, los estudios no son concluyentes, por lo que solo se contraindicarán
cuando haya riesgo de cáncer de mama por factores genéticos.

En el cáncer de endometrio tiene que ver con factores de riesgo principalmente

asociados al síndrome metabólico, diabetes, hipertensión, cáncer, dislipidemia.
Por lo que al corregir los factores de riesgo, podemos utilizarlos para regular el
ciclo y generar la descamación del endometrio.

Con respecto al cáncer de ovario, se sabe que el uso de anticonceptivos durante

5 años seguidos, disminuye su riesgo, lo mismo para el cáncer colorrectal, sobre
todo cuando se combina con el cáncer de ovario. En el cáncer de cérvix que tiene
como factor de riesgo principal al VPH, por lo que si la paciente tiene VPH de
alto riesgo y sea fumadora, hace que no sea candidata para anticonceptivos
hormonales combinados.

Varios estudios, especialmente metanálisis, para cáncer de ovario, cáncer de

endometrio y ciertos tipos de cáncer colorrectal, sobre todo el asociado con el
síndrome de Lynch, han demostrado que los anticonceptivos tienen un papel
importante en la prevención.

Conclusiones
Las hormonas se deben usar siempre a favor de las pacientes,
independientemente del proceso anticonceptivo. Es importante hacer hincapié
los beneficios adicionales. Recordarle a la paciente que una vez que se suspende
su uso, no es necesaria la “desintoxicación”. Entre 24 a 72 horas, la depuración va
a ser casi completa.

Si no se restituye inmediatamente la menstruación, hay que buscar una

disfunción ovárica, ver la edad de la paciente, revisar el endometrio y otros
factores que puedan estar alterando su ciclo.

En el caso de que la paciente no sea constante con su toma hormonal, hacer una
prueba de embarazo, y recordarle que el anticonceptivo combinado no genera
ningún riesgo en el embarazo.

Recordando que las progesteronas son las que dan la pauta para verificar cuál
es el que le beneficia o le favorece más a nuestro paciente.
 Personal view

More than just contraception: the

impact of the levonorgestrel-­
releasing intrauterine system on
public health over 30 years
Kristina Gemzell-­Danielsson,1 Ali Kubba,2 Cecilia Caetano,3
Thomas Faustmann,4 Eeva Lukkari-­Lax,5 Oskari Heikinheimo ‍ ‍6

1
Department of Women’s & ABSTRACT gender equality. Universal access to SRH
Children’s Health, Karolinska
Universal access to sexual and reproductive services is essential to achieving this objec-
Institutet, and Karolinska
University Hospital, Stockholm, health services is essential to facilitate the tive.1 2 Increasing access to modern, effec-
Sweden empowerment of women and achievement of tive methods of contraception can reduce
2
Department of Gynecology, gender equality. Increasing access to modern the incidence of unplanned pregnancy,
Guys and St Thomas NHS
Foundation Trust, London, UK
methods of contraception can reduce the decrease maternal mortality, and can also
3
Medical Affairs, Bayer Consumer incidence of unplanned pregnancy and decrease contribute to fighting poverty.1 3 4
Care AG, Basel, Switzerland maternal mortality. Long-­acting reversible Long-­ acting reversible contraceptives
4
Medical Affairs, Bayer AG, Berlin, contraceptives (LARCs) offer high contraceptive (LARCs), such as implants, and hormonal
Germany
5
Clinical Development, Bayer Oy,
efficacy as well as cost-­efficacy, providing and non-­ hormonal intrauterine devices
Espoo, Finland benefits for both women and healthcare (IUDs), are not only highly effective at
6
Department of Obstetrics systems. The levonorgestrel-­releasing intrauterine preventing unintended pregnancy and
and Gynecology, University of system (LNG-­IUS) first became available in subsequent abortion but are also cost-­
Helsinki and Helsinki University
Hospital, Helsinki, Finland 1990 with the introduction of Mirena (LNG-­ effective options that provide benefits for
IUS 20), a highly effective contraceptive which both women and healthcare systems.
Correspondence to can reduce menstrual blood loss and provide Mirena (Bayer AG, Berlin, Germany)
Dr Cecilia Caetano, Medical other therapeutic benefits. The impact of the was the first levonorgestrel-­ releasing
Affairs, Bayer Consumer Care AG, LNG-­IUS on society has been wide ranging, intrauterine system (LNG-­IUS) of its kind.
4002 Basel, Switzerland; ​cecilia.​
caetano@​bayer.​com including decreasing the need for abortion, Developed by the Population Council’s
reducing the number of surgical sterilisation International Committee for Contracep-
Received 18 November 2020 procedures performed, as well as reducing the tion Research, Mirena (also termed LNG-­
Revised 12 January 2021
Accepted 13 January 2021
number of hysterectomies carried out for issues IUS 20 based on the average in vivo LNG
Published Online First such as heavy menstrual bleeding (HMB). In the release rate over the first year5) became
29 January 2021 context of the COVID-19 pandemic, Mirena can available in 1990 in Finland under the
provide a treatment option for women with name Levonova. Mirena is a highly effec-
gynaecological issues such as HMB without tive contraceptive, with a long-­lasting but
organic pathology, minimising exposure to the reversible effect that does not require a
hospital environment and reducing waiting times daily routine. It also reduces menstrual
for surgical appointments. Looking to the future, blood loss, which women often find bene-
research and development in the field of the ficial. Additionally, Mirena has thera-
LNG-­IUS continues to expand our understanding peutic benefits; it is an effective treatment
of these contraceptives in clinical practice and for heavy menstrual bleeding (HMB)
offers the potential to further expand the choices without an organic cause and dysmenor-
© Author(s) (or their available to women, allowing them to select the rhoea, as well as providing endometrial
employer(s)) 2021. Re-­use option that best meets their needs. protection for peri- and postmenopausal
permitted under CC BY-­NC. No
women receiving menopausal hormone
commercial re-­use. See rights
and permissions. Published by therapy.
BMJ. BACKGROUND The impact of the LNG-­IUS on society
To cite: Gemzell-­Danielsson K,
Sexual and reproductive health (SRH) has been wide ranging: from decreasing
Kubba A, Caetano C, et al. BMJ constitutes a fundamental human right the need for abortion (ie, unwanted
Sex Reprod Health and plays a vital role in the empower- pregnancy),6 7 to reducing the number
2021;47:228–230. ment of women and helping achieve of surgical sterilisation procedures

228     Gemzell-­Danielsson K, et al. BMJ Sex Reprod Health 2021;47:228–230. doi:10.1136/bmjsrh-2020-200962

 Personal view

performed,8 as well as reducing the number of hyster- economic burden both to women and the healthcare
ectomies carried out for issues such as HMB without system.
an organic cause,9 10 allowing women to avoid an inva- By decreasing the amount of sanitary protection,
sive surgical procedure and maintain their fertility. packaging and other waste products, the LNG-­ IUS
and other long-­acting methods can also be seen as
NOW MORE THAN EVER: THE ROLE OF LARCS IN ‘green contraceptives’ that reduce the traffic of non-­
THE CHANGING HEALTHCARE LANDSCAPE biodegradable items to landfill sites.
With the COVID-19 pandemic causing widespread
disruption to the provision of healthcare, including
contraceptive services and supply chains, there are THE FUTURE OF THE LNG-IUS AND PUBLIC
bound to be concerns regarding the potential for HEALTH
increased unintended pregnancies.11 With the popularity of LARCs, especially the LNG-­
Unlike short-­ acting methods such as oral contra- IUS, continuing to increase it is good to know that
ceptive pills, long-­ acting methods provide effective research in this field is keeping pace. Real-­ world
contraception for years after a single intervention that studies continue to deepen our understanding of
can mitigate concerns regarding access to and avail- how the LNG-­IUS performs in clinical practice and
ability of contraceptive services. further controlled trials offer the potential to expand
As we seek to preserve capacity in healthcare systems or extend its use. Additionally, next-­generation IUDs
and save valuable resources while increasing access are being explored, which could further expand
to all, a shift towards medical treatment delivered in the options available to women, allowing them to
community settings for issues such as HMB is taking choose the method that is best suited to their needs.14
place in clinical practice. Medical options are less inva- Moving forward, it seems reasonable to hope that
sive than surgical treatments, generally preserve fertility, with further developments and ongoing initiatives,
and in most cases can be prescribed and implemented access to LARCs will become a possibility for women
rapidly and easily. In the context of the COVID-19 across the globe.
pandemic, the therapeutic benefits of Mirena provide
an option for treating women with conditions such as Contributors Kristina Gemzell-­Danielsson, Ali Kubba, Oskari
Heikinheimo and Cecilia Caetano developed the concept
HMB without an organic cause or dysmenorrhoea that for the manuscript. Thomas Faustmann and Eeva Lukkari-­
minimises exposure to the hospital environment and Lax critically reviewed and refined the concept. All authors
reduces lengthy waits for surgical appointments. reviewed each subsequent draft and provided detailed
feedback. All authors reviewed and approved the final draft for
BEYOND GYNAECOLOGICAL PRACTICE: HOW submission.
EFFECTIVE CONTRACEPTION CAN EMPOWER Funding The authors would like to acknowledge Highfield,
Oxford, UK for providing medical writing assistance with
WOMEN
funding from Bayer AG.
Increasing awareness and access to contraception
Competing interests Kristina Gemzell-­Danielsson has been an
can help women in low-­ income settings, by miti- ad hoc advisory board member or invited to give presentations
gating poverty and challenging gender inequalities. for Merck (MSD), Bayer, Exelgyn, Actavis, Gedeon Richter,
By providing discrete, effective contraception and Mithra, Exeltis, Ferring, Natural Cycles, Azanta, Gynuity,
reducing menstrual bleeding in the majority of users, Campus Pharma and HRA-­Pharma. Oskari Heikinheimo serves
occasionally on advisory boards for Bayer AG, Gedeon Richter,
the LNG-­IUS can facilitate women’s increased produc-
Sandoz and Vifor Pharma, and has lectured at educational
tivity and participation in society, as well as reducing events organised by these companies. Ali Kubba has taken
some of the issues caused by limited access to sanitary part in sponsored educational activity and served on advisory
protection (menstrual poverty) and providing freedom boards for pharmaceutical companies including Bayer, Merck
from social stigma and exclusion. and Exeltis. Thomas Faustmann is an employee of Bayer AG,
Berlin, Germany. Cecilia Caetano is an employee of Bayer
Effective contraception for women living with Consumer Care AG, Basel, Switzerland. Eeva Lukkari-­Lax is an
comorbidities, such as HIV/AIDS or anaemia, is also employee of Bayer Oy, Espoo, Finland.
vital to ensure a well-­ timed pregnancy that occurs Patient and public involvement Patients and/or the public
when they are in optimal health and is not associated were not involved in the design, or conduct, or reporting, or
with further negative health consequences. Not only dissemination plans of this research.
does Mirena contribute to preventing unplanned preg- Patient consent for publication Not required.
nancy in these women, but the associated decrease in Provenance and peer review Not commissioned; externally
menstrual blood loss can have the additional benefit of peer reviewed.
reducing exposure to infected blood in the context of Open access This is an open access article distributed in
HIV/AIDS,12 13 and improving the body’s iron stores in accordance with the Creative Commons Attribution Non
the context of anaemia. Commercial (CC BY-­NC 4.0) license, which permits others
to distribute, remix, adapt, build upon this work non-­
The reduced number of visits to healthcare providers commercially, and license their derivative works on different
(eg, to obtain repeat prescriptions) and reduced need terms, provided the original work is properly cited, appropriate
to purchase sanitary protection also decreases the credit is given, any changes made indicated, and the use is non-­

Gemzell-­Danielsson K, et al. BMJ Sex Reprod Health 2021;47:228–230. doi:10.1136/bmjsrh-2020-200962 229

 Personal view
commercial. See: [Link] 7 Pohjoranta E, Suhonen S, Gissler M, et al. Early provision
0/. of intrauterine contraception as part of abortion care–5-­
year results of a randomised controlled trial. Hum Reprod
ORCID iD
Oskari Heikinheimo [Link] 2020;35:796–804.
8 Grimes DA, Mishell DR. Intrauterine contraception as an
alternative to interval tubal sterilization. Contraception
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Empowering women: promoting access to contraception in intrauterine system (Mirena): an emerging tool for
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atti/​Resolution_​2331_(​2020)_​ENG.​pdf [Accessed 11 Sep Health 2015;6:26–30.
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from the States Brookings Institution, 2019. Available: https:// releasing intrauterine system (LNG-­IUS) in HIV-­infected
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International Journal of Women’s Health Dovepress
open access to scientific and medical research

Open Access Full Text Article

REVIEW

Contraception During Perimenopause: Practical

Guidance
Giovanni Grandi 1 , Pierluigi Di Vinci 2 , Alice Sgandurra 1 , Lia Feliciello 1 , Francesca Monari 1 ,
Fabio Facchinetti 1
1
Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio Emilia, Azienda Ospedaliero
Universitaria Policlinico, Modena, 41124, Italy; 2International Doctorate School in Clinical and Experimental Medicine, Department of Biomedical,
Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, 41124, Italy

Correspondence: Giovanni Grandi, Department of Medical and Surgical Sciences for Mother, Child and Adult, University of Modena and Reggio
Emilia, Azienda Ospedaliero Universitaria Policlinico, Via del Pozzo 71, Modena, 41124, Italy, Tel +39 059 422 2665, Email [Link]@[Link]

Abstract: Climacteric is by no means in itself a contraindication to safe contraception. On the contrary, there are several conditions
related to the perimenopause that could benefit from the use of modern contraceptives, mainly hormonal, with the goals of avoiding
unintended pregnancies and giving further possible benefits beyond contraception (menstrual cycle control, a reduction of vasomotor
symptoms and menstrual migraines, a protection against bone loss, a positive oncological risk/benefit balance). This narrative review
aims to provide practical guidance on their possible use in this particular life stage, both short- and long-acting reversible contra­
ceptives, and to assist clinicians for women transitioning from contraception to their menopausal years, including the possible
initiation of postmenopausal hormone therapy. Comprehensive contraceptive counselling is an essential aspect of the overall health
and wellbeing of women and should be addressed with each such patient irrespective of age.
Keywords: contraception, perimenopause, SARCs, LARCs, oral contraceptives, combined oral contraceptives, vaginal rings, patch,
intrauterine devices, implants, forties, metabolism

Contraception in Perimenopause: Is There Need or Not?

The perimenopause is the period that precedes the menopause and is roughly a synonym of “menopausal transition”. It
corresponds to the stages −1 and −2 according to the STRAW+10 Staging System for Reproductive Aging in Women,1
beginning when there is a variable persistent length of ≥7-day difference of consecutive menstrual cycles plus supportive
clinical and endocrinological criteria.1
It starts 5–10 years before the menopause, at approximately 40 years of age.2 Since the population is aging, the total
number of women aged 40–49 years is increasing by 32% in Europe. As defined by the Stages of Reproductive Aging
Workshop (STRAW) criteria, the term perimenopause or menopausal transition covers the transition from reproductive
age through to menopause, ie, early perimenopause (stage −2), late perimenopause (stage −1), the last menstrual period
(stage 0) and early post-menopause (stage +1).3 The principal criteria for entry into the early perimenopause include the
onset of irregular or “variable length” cycles with at least 7-day differences in cycle length between consecutive cycles or
a cycle length <25 days or >35 days. Late perimenopause starts once the cycles exceed 60 days in length.
This period is characterised by several changes in the hormonal milieu of a woman: a reduction in the number of
primordial follicles is demonstrated due to the lower levels of inhibin B and Anti-Müllerian Hormone (AMH)4 and the
ovaries begin to decrease in weight and size.5 This is associated with an increase in follicle stimulating hormone (FSH)
levels due to the decrease in oestradiol (E2) and inhibin B in the serum, which are fundamental to its negative feedback,
while progesterone levels control luteinising hormone (LH).5 Moreover, the low levels of E2 cannot induce the LH peak
that is necessary for ovulation. Therefore, due to these hormonal changes, the occurrence of anovulatory cycles increases
and the interval between two ovarian cycles tends to be variable in length.6 The result is that the fertility of a woman
during the perimenopause is lower but, at the same time, there are higher rates of unintended pregnancies among these

International Journal of Women’s Health 2022:14 913–929 913

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 Grandi et al Dovepress

Voluntary Abortion in Emilia-Romagna (Italy)

18
16
14
12
10
% 8
6
4
2
0
15-19 20-24 25-29 30-34 35-39 40-44 45-49
2010 2020

Figure 1 Comparisons between the percentage of voluntary abortions between 2010 and 2020 according to the different age groups in the Emilia-Romagna region (Italy).
Notes: Data from: Regione Emilia-Romagna. Salute. Assessorato politiche per la salute; Relazione sull’interruzione volontaria digravidanza in Emilia-Romagna nel 2020
[Health Policy Department; Report on the voluntary termination of pregnancy in Emilia-Romagna in 2020]; 2021. Available from: [Link]
siseps/applicazioni/ig/documentazione. Accessed February 1, 2022. Italian.101

women.7 Women over 40 have lower fecundity (chance of a live birth per menstrual cycle) compared with their younger
cohort. The annual risk of pregnancy is clearly lower than that in younger women: 10% at 40–44 years to only 2–3% at
45–49 years.8 Although the risk of pregnancy is lower in this age group, the acceptance of pregnancy is also reduced with
more women having elective abortions, so there is an important need for contraception. In 2006, the overall rate of
unintended pregnancy in the United States was 49%, of which 48% represents women aged 40–44.9
In Italy, the abortions in this lifestage (>40 years old) were 8140 out of 65,757 total abortions in 2020 (12%) (http://
[Link]/[Link]?DataSetCode=DCIS_IVG_CARATTDON). This is the only phase of life in which abortions are
not significantly decreasing from 2010 to 2020 in our Italian region, Emilia-Romagna (Figure 1) ([Link]
[Link]/siseps/applicazioni/ig/documentazione). In addition, these “late” pregnancies can be complicated by
several factors, such as higher risk of miscarriages, chromosomal abnormalities (due to the poorer quality of oocytes
generated in metaphase over 40 years10), ectopic pregnancy, preeclampsia and post-partum haemorrhage risk.11 In 2011,
women aged 40–44 experienced spontaneous abortion at a rate of 34%, while women aged 45 and older reported a rate of
53% for ongoing pregnancies. Moreover, the age-related issues associated with the use of hormonal therapies must be
analysed.12 Importantly, among them is the increased risk of cancer, the possible occurrence of osteopenia and
osteoporosis, the risk of thromboembolism, psychological changes and the possible sexual dysfunction associated with
this peculiar late reproductive period.13 Regarding the thromboembolic risk, it is strictly related to hypertension and
cardiovascular diseases in general, as well as obesity and metabolic syndrome, whose incidence rises with age.14
Finally, another important problem often experienced during the climacteric period is represented by the abnormal­
ities related to abnormal uterine bleeding (AUB), due to both organic and dysfunctional factors,15 which have a strong
impact on the woman's life.16 Therefore, in the fourth and fifth decades of life in women there is a noticeable incidence of
adenomyosis, polyps and fibroids, which are possible organic causes of AUB.17 Among the spectrum of perimenopausal
uterine alterations, it is important to include endometrial hyperplasia, a condition that is characterised by morphological
alterations in the ratio of endometrial glands/stroma.18 This disease frequently occurs after forties and the risks cannot be
underestimated.
There are several conditions related to the perimenopause that could benefit from the use of modern contraceptives,
mainly hormonal, with the goals of avoiding unintended pregnancies and providing further benefits beyond contra­
ception. Fertility awareness-based methods are unreliable during the perimenopause because of unpredictable ovulation
and cycles, as described above; therefore, they should not be utilised during this time. We will therefore detail the
contraceptive options available to women over 40 and, also, the unique contraceptive and non-contraceptive benefits and
health risks associated with different contraceptive methods in this population. Indeed, contraceptive use has recently
been found to be relatively stable over time, with short-acting hormonal contraception and condoms being the most

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common contraceptive methods until women reach the age of 40–45 years when long-acting reversible contraceptives
(LARCs) and permanent contraception become the most prevalent.19
In general, according to the International Medical Eligibility Criteria for Contraceptive Use, there is no single
contraceptive choice contraindicated based on age alone20 because there is no evidence to suggest that age itself is
a risk factor for contraceptive-related complications. However, with age comes an increased risk of some medical
conditions, including obesity, hypertension, diabetes, hyperlipidaemia and cancer, which have to be considered as
independent risk factors.
The aim of this narrative review is to give practical guidance on their possible use in this particular life stage, by
separately describing Short- and Long-Acting Reversible Contraceptives (SARCs and LARCs, respectively) and to assist
clinicians for women transitioning from contraception to their menopausal years, including the possible initiation of
postmenopausal hormone therapy (HT). Comprehensive contraceptive counselling is an essential aspect of the overall
health and wellbeing of women and should be addressed with each such patient irrespective of age. A practical guide to
this particular medical counselling is reported in Box 1.

Box 1 Practical Guidance for Contraception Use in Perimenopause

SARCs
Combined Oral Contraceptive (COC)
● All doses of COCs are still appropriate for use in all otherwise healthy, perimenopausal women.
● Check the WHO Guidelines19 for eligibility (excluding smoking, hypertension, migraine, systemic lupus erythematosus with antiphospholipid
antibodies, thrombosis history, known thrombogenic mutations, etc.).
● Possible use in Virgo women.
● Prefer products containing estradiol (quadriphasic estradiol valerate/dienogest, monophasic estradiol/nomegestrol acetate), in particular as the
first CHC prescription.40,42,43
Possible extra-contraceptive benefits
● Menstrual cycle control.
● Reduction of primary/secondary dysmenorrhea.
● Treatment of women with endometriosis.95
● Reduction of vasomotor symptoms, such as hormone-related headaches or menstrual migraines.
● Protection of bone health.
● Reduction of endometrial, colorectal and ovarian cancer risk.
Vaginal Ring
● Check the WHO Guidelines19 for eligibility (excluding smoking, hypertension, migraine, systemic lupus erythematosus with antiphospholipid
antibodies, thrombosis history, known thrombogenic mutations, etc.).
● Consider in women who desire to avoid daily pill intake/forgetful.
Possible extra-contraceptive benefits
● Menstrual cycle control.
● Reduction of primary/secondary dysmenorrhea.
● Treatment of women with endometriosis.95
● Reduction of vasomotor symptoms, such as hormone-related headaches or menstrual migraines.
● Protection of bone health.
● Improvement in vaginal lubrication.
● Improvement in lactobacillus species in vaginal flora.96
Patch
● Check the WHO Guidelines19 for eligibility (excluding smoking, hypertension, migraine, systemic lupus erythematosus with antiphospholipid
antibodies, thrombosis history, known thrombogenic mutations, etc.).
● Possible use in Virgo women.
● Consider in women who desire to avoid daily intake/forgetful.
● Its use in this age group is infrequent/not preferable (higher estrogen levels).97
Possible extra-contraceptive benefits
● Menstrual cycle control.
● Reduction of primary/secondary dysmenorrhea.

(Continued)

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Box 1 (Continued).

● Treatment of women with endometriosis.95

● Reduction of vasomotor symptoms, such as hormone-related headaches or menstrual migraines.
● Protection of bone health.
Progestin-only pill (POP)
● Check the WHO Guidelines19 for eligibility (excluding personal history of active or recent (within 5 years) breast cancer or lupus erythematosus
with positive or unknown antiphospholipid antibodies, etc.).
● Possible use in Virgo women.
● Consider in women with a contraindication to oestrogens.
Possible extra-contraceptive benefits
● Menstrual cycle control (unpredictable, possible amenorrhea).
● Reduction of primary/secondary dysmenorrhea.
● Treatment of women with endometriosis.95
● Possible reduction of menstrual migraines.
LARCs
● Cu-IUD
● Check the WHO Guidelines19 for eligibility (excluding distorted uterine cavity, current pelvic inflammatory disease, purulent cervicitis, chlamydial
infection or gonorrhoea, Wilson syndrome, etc.).
● Avoid in women with heavy menstrual bleeding.
● Consider in women who should avoid exposure to hormones, eg, [hormone fears and misconceptions or with contraindications to oestrogen and
progestin assumption (eg, breast cancer survivors)].
Possible extra-contraceptive benefits
● Reduction of endometrial, cervical and ovarian cancer risk.
● Possible use as an emergency contraceptive.
Implant
● Check the WHO Guidelines19 for eligibility [exclude personal history of active or recent (within 5 years) breast cancer or lupus erythematosus
with positive or unknown antiphospholipid antibodies, etc.].
● Possible use in Virgo women who desire LARC use.
● Consider in women with BMI >30 and metabolic diseases.
● Consider in women with contraindication of oestrogens.
Possible extra-contraceptive benefits
● Menstrual cycle control (unpredictable/possible amenorrhea).
● Reduction of primary/secondary dysmenorrhea.
● Treatment of women with endometriosis.95
Depot medroxyprogesterone acetate (DMPA)
● Check the WHO Guidelines19 for eligibility (excluding personal history of active or recent (within 5 years) breast cancer or lupus erythematosus
with positive or unknown antiphospholipid antibodies, etc.).
● Possible use in Virgo women
● Its use in this age group is infrequent/not preferable (negative effect on bone health).65
LNG-IUS
● Check the WHO Guidelines19 for eligibility (excluding personal history of active or recent (within 5 years) breast cancer or lupus erythematosus
with positive or unknown antiphospholipid antibodies, distorted uterine cavities, etc.).
● Consider in women with a contraindication to oestrogens
Possible extra-contraceptive benefits
● Menstrual cycle control.
● Reduction of primary/secondary dysmenorrhea.
● Treatment of women with endometriosis.95
● Treatment of abnormal uterine bleeding without an organic cause (on-label).
● Treatment of women with fibroids (not distorting the endometrial cavity) and adenomyosis (off-label).
● Prevention/treatment of endometrial polyps.
● Prevention/treatment of endometrial hyperplasia/endometrial intraepithelial neoplasia.
● Possible use as a progestin component for postmenopausal hormone therapy (on-label).
● Reduction of endometrial, cervical and ovarian cancer risk.

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Short-Acting Reversible Contraceptives (SARCs)

Combined Hormonal Contraceptives (CHCs)
CHCs are available as a daily pill [combined oral contraceptives (COCs)], a weekly transdermal patch, a monthly vaginal ring
(three weeks of use) and in few countries (US, Latin America) some monthly injectable combined contraceptives. These methods
are made with an estrogenic component (“combined”), such as ethinyl-oestradiol (EE), E2, a natural oestrogen and, more
recently, oestetrol (E4), in combination with many progestins, which can be derived from natural progesterone, from 19 nor-
testosterone or by spironolactone.21
The general mechanism of action of these contraceptives is to inhibit ovulation, stabilise endometrial proliferation and
modify the cervical mucus in order to make it inhospitable for the ascent of spermatozoa.22 CHCs are highly effective when
correctly used, but they are prone to a higher risk of user failure due to the necessity of regular intake, so there is a significant
difference between ideal use and typical use for contraceptive effectiveness. Perfect use failure rate is 0.3% and typical use
failure rate is up to 7–9% in reproductive-age women. However, this difference is not as high in perimenopausal women
compared to younger women due to the physiological decline of natural fertility.23 In the last 60 years, important develop­
ments in CHC technologies have been achieved, guaranteeing women more choices than in the past while maintaining/
improving contraceptive efficacy: nowadays, new formulations of CHCs are available on the market with very low oestrogen
doses as well as natural oestrogens (E2 and E4) and progestins without many of the androgenic side effects.21
A recent meta-analysis of 18 RCTs comparing the patch, ring and COCs found no significant differences in
contraceptive effectiveness, indications and contraindications between the different SARCs.24
For women in perimenopause, CHC use offers, beyond a valid contraceptive method, potential additional benefits such as:

● satisfactory menstrual control, which avoids AUB, resulting in regular menstrual bleeds and further reducing
dysmenorrhea and pelvic pain.25
● A reduction of vasomotor symptoms, such as hormone-related headaches or menstrual migraines, which occur in
more than 60% of perimenopausal women, especially during a hormone-free interval (HFI).17,25,26
● Protection against bone loss via two mechanisms: preventing bone demineralisation, which is very important in this
life-stage, and enhancing bone mineral density, even at low doses.27
● A reduction of endometrial, colorectal and ovarian cancer risk, close to their peak incidence.28

Overall, CHCs are still appropriate for use in all otherwise healthy, perimenopausal women.
The advantages of CHCs use in comparison to progestin-only contraceptives use are reported in Figure 2.

COMBINED PROGESTIN-ONLY

• Contraception • Contraception
• Menstrual cycle regulation • Menorrhagia and dysmenorrhea treatment
• Menorrhagia and dysmenorrhea treatment • Possible menstrual migraine reduction
• Vasomotor symptoms and menstrual migraine reduction • Endometrial hyperplasia prevention
• BMD protection • Oncological protection (ovary, endometrium)?
• Endometrial hyperplasia prevention
• Oncological protection (ovary, endometrium, colon-rectum) • No menstrual cycle regulation (possible amenorrhea)
• No vasomotor symptoms and menstrual migraine
reduction
• No BMD protection

Figure 2 Pros and cons of the use of combined hormonal contraceptives (CHCs) or progestin-only contraceptives in the perimenopause.

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COCs
COCs are the most commonly used hormonal contraceptives worldwide and remain a valid option thanks to their
flexibility, convenience and well-known non-contraceptive benefits. COCs are available in:

● cyclic regimens, composed of 21 active pills and 7 inactive pills/no assumption

● a shortened HFI regimen, composed of 24–26 active pills and 2–4 inactive pills
● an extended regimen, which includes 84 active pills and 7 inactive pills
● a continuous regimen, which is made up of a 365 active pill regimen

The shorter the scheduled menstrual interval is, the less vasomotor effects, menstrual migraine and abnormal menstrual
bleeding shall occur. Clinical experience shows that the continuous use of all types of COCs is effective in reducing
blood loss.29 This reduction also seems to be influenced by the dosage of EE; in fact, it is greater with 30–35 µg
compared to 20 µg30 and the type of oestrogen administered. Recent studies have demonstrated that even COCs with E2
seem to act very effectively in the management of heavy menstrual bleeding (HMB). In particular, it has been seen that
the quadriphasic combination of oestradiol valerate (E2V) and dienogest has an important effect in reducing HMB, with
a reduction of between 80 and 120 mL of blood per menstrual cycle.31

COCs, Vasomotor Symptoms and Menstrual Migraine

There is some evidence about the role of CHCs to also improve vasomotor symptoms: hot flushes could already appear in
the premenopausal period and are effectively reduced by CHC use. For women who have already experienced the first
symptoms of menopause during this period, COC therapy appears to be a more accepted option than postmenopausal
hormone therapy (HT). One study evaluated COCs with an alternative option for oestrogen exposure during the usual
placebo week: one group received 10 µg of EE for 5 days with 2 days of placebo and the other group received traditional
placebo pills for 7 days. All women reported a decrease in somatic, anxiety and depression symptoms. In the group
treated with additional oestrogen, there was an even larger decrease in vasomotor symptoms, depression, somatic
symptoms and sexual dysfunction compared with those who received placebo during the hormone-free week.32
During perimenopause, migraine frequency and severity increase, particularly in women with menstrual migraine.
This may partly be because menstruation and consequently menstrual migraine are more frequent as the cycle length
shortens. Women with migraine also have a significantly increased risk of vasomotor symptoms, anxiety and depression,
as well as sleep disturbance, further increasing morbidity. On the contrary, post-menopause, the prevalence of migraine
without aura declines. In contrast, migraine with aura is not directly affected by menopause and headache becomes less
of a feature of attacks with increasing age.33 In theory, continuous COC use, which suppresses ovarian activity as well as
menstrual bleeding, should effectively manage hormonal migraine triggers. However, there are only limited clinical trial
data regarding migraine. The European Headache Federation (EHF) and the European Society of Contraception and
Reproductive Health (ESCRH) recommend COCs for women with migraine who require contraception, experience
oestrogen-withdrawal headaches, or benefit from treatment with COCs for medical reasons.34 In all cases, continuous use
is advised to prevent oestrogen-withdrawal migraine triggered during breaks. If breaks are necessary to control
unscheduled bleeding, they should be shortened to four days. CHCs can be used by women with migraine without
aura but are contraindicated for contraceptive use in women with migraine with aura since both COCs and aura are
independent risk factors for ischemic stroke.

COCs and Bone Mineral Density

There are still no reliable data in the literature about the effect of COC on bone mineral density (BMD): in general, CHC
use does not seem to exert any significant, nor detrimental or protective, effect on bone in the general population.35 While
the strongest beneficial effect of CHCs on BMD was seen in perimenopausal women with low oestrogen levels, it is still
not clear whether this effect might mitigate fracture risk.27

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COCs and Cardiovascular Risk

The relative risk of thromboembolic diseases increases slightly in COC users, which is about two to three times higher
than in non-users. However, the greatest risk occurs within the first 3 months of initiation (OR 12, 95% CI 7.1–22.4).36
The incidence of VTE sharply increases after age 40, thus demonstrating that age plays an important role. A meaningful
Danish cohort study found that the incidence of VTE in COC users rose from 8.7 per 10000 women-years for women
aged 30–34 to 20.8 per 10000 women-years for women aged 45–49.37 Another large case–control study found that the
incidence rate of VTE in COC users increased by nearly 3-fold between the ages 20–29 and over 40.38 The risk of VTE
in patients using COCs is influenced by both the type of progestin and the dose of oestrogen contained. A study
performed by Sugiura et al shows that COCs with 20 µg of EE have a lower risk of pulmonary embolism and serious
arterial thromboembolic events than COCs with 30–40 µg EE. In addition, using COC-containing levonorgestrel (LNG)
is associated with a 50% lower risk of pulmonary embolism (PE) compared with using a COC with a third-generation
progestin.39 The absolute risk of thrombotic stroke (TS) and myocardial infarction (MI) associated with COC is low in
women of reproductive age but increases with age, EE dose and the presence of additional cardiovascular risk factors
such as smoking, hypertension, diabetes, obesity and hyperlipidaemia.7 However, during counselling, the increased
maternal morbidity and mortality of pregnancy related to older age should be addressed, including the fact that any
particular contraindication of hormonal contraceptives also increases the risk of significant adverse events during
pregnancy.
The incidence of TS and myocardial infarction (MI) was 20- and 100-times higher in an older cohort (aged 45–49
years) versus a younger cohort (aged 15–19 years) of Danish women, respectively; also, considering COC use, the
overall risk of stroke increases by 2.2-times and that of MI by 2.3-times.37 A significantly increased risk of TS in women
who use CHCs was also shown in a Cochrane review40 including 24 observational studies. The dose of EE seems to
influence the risk of TS and MI. The Cochrane review found the relative risk of stroke and MI to increase from 1.6 (95%
CI 1.4–1.8) for 20 μg EE to 2.0 (95% CI 1.4–3.0) for 30–50 μg EE; also, the Danish study had comparable, but non-
significant findings, with an RR of 1.6–1.9 for current COC use depending on EE dose.37
In recent years, COCs containing E2 rather than EE have been developed.41 The most important exponents are
a quadriphasic preparation containing E2V+dienogest (DNG) and a monophasic preparation containing micronised E2
+nomegestrol acetate (NOMAc). Both have a short HFI, which results in better menstrual cycle control. It seems that
using an estrogenic component identical to the natural one might offer a safer alternative to the traditional pill containing
EE. These preparations share some similarities with postmenopausal HT preparations, rather than COCs, and so have
theoretical safety benefits for women over 40. However, there is currently insufficient evidence to define a specific
recommendation for the use of these preparations in women over 40. Preparations containing natural E2 seem to be more
neutral than those with EE due to their theoretical safety benefits for women over 40 years of age; in the Expert Opinion
of the authors, these are clearly the first-line choice between different CHCs in these women, especially if non-oral
methods of E2 administration will be soon available.42
Noteworthy, WHO eligibility criteria do not report differences between E2 and EE-containing products,19 but, it is
assumed that there could be a risk difference between diverse oestrogen components (EE versus E2). The INAS SCORE
study by Dinger et al shows that COC containing E2V and DNG is associated with a similar or even lower cardiovascular
risk compared to COCs containing LNG or other progestins.43 A similar recent large post-marketing study that includes
a total of 101,498 women, with 49,598 using E2-NOMAc and 51,900 using EE-LNG for up to 2 years, has found a risk
of VTE and PE in NOMAc-E2 which is similar to or even lower than that of LNG-based COCs users [HR adjusted of
0.59 (95% CI 0.25–1.35) (adjusted for age, BMI, family history of VTE and current duration of use)].44

COCs and Oncological Risk

The RR of both ovarian cancer and endometrial cancer is significantly reduced when using COCs; this protective effect
increases with the duration of therapy and remains several decades after its interruption. A systematic review shows that
the risk of ovarian cancer is reduced by at least 50% with COC use (<40 µg EE)45 and another collaborative reanalysis of

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45 epidemiological studies found a 20% reduction in ovarian cancer risk for every 5 years of COC use.46 This effect was
more evident if COCs have been used near the peak of incidence of ovarian cancer, precisely the perimenopause.45
For these reasons, COCs could be used as a chemoprophylactic strategy for younger women with a BRCA1 or
BRCA2 gene mutation.47 Observational studies have also shown a reduction in functional ovarian cysts and benign
ovarian tumours development in COC users,48 which are very common in this life stage.
The risk reduction for endometrial cancer is between 50% and 70%; in particular, the risk reduction in endometrial
and serous serotypes is greater than in the mucinous one.49 In women using COCs for at least 12 months, the protection
could last for at least 15 years after discontinuation.50
There is little evidence regarding CHC use and breast cancer risk, related specifically to women aged over 40. The
increased risk is basically age-related: if the risk of developing breast cancer at 35 years is 1/500, it is 1/100 at 40.51
Studies with older COC formulations (higher-dose) found a slightly increased risk of breast cancer (with RR in the range
1.24–1.30) that declines gradually after cessation, with no significant risk of breast cancer after 10 years of non-use.28
However, nowadays, with the use of low-dose pills, this risk does not seem to exist or to be minimal at most: one meta-
analysis of five cohort studies found a very small but significant increase in breast cancer risk for every 5 (RR 1.07, 95%
CI 1.03–1.11) and 10 (RR 1.14, 95% CI 1.05–1.23) years of use.51
In the Danish study, the RR of developing breast cancer for recent and current users of any hormonal contraceptive
(mostly utilising COCs) is 1.20 (95% CI 1.14–1.26, p = 0.002). This means one extra breast cancer per 7690 women
using a CHC for one year.52 Importantly, the study has some limitations regarding other important confounding factors
for breast cancer risk: in particular, the BMI is not known for all patients while breastfeeding, family history or other
oncological risks were not included in the analysis.
For BRCA1/BRCA2 carriers, who themselves have an increased baseline risk, there does not appear to be an
additional risk associated with COC use.53
It is important to take in mind that the specific benefits/risks ratio according to these specific topics (cardiovascular
and oncological risk) can additionally change between different ages of reproductive years and between starters and long-
term COC users:51 then, counselling should be personalised.11 Some risks differ if COC use begins in middle age or if
use is continued from a young age. The thrombotic risk increases with age and is greatest in the first months of use.
Additionally, the presence of other cardiovascular risk factors (eg, obesity, smoking, hypertension, and diabetes) high­
lights the importance of eligibility criteria and may even contraindicate the use of COC. On the other hand, the risk of
cervical cancer should increase after continuous use for more than five years in women with human papillomavirus,
while data about the cumulative risk of breast cancer data are conflicting.54

Vaginal Ring
The contraceptive ring is a type of CHC that does not involve a daily intake. It can be used cyclically (in for 3 weeks, out
for 1 week) or continuously (in for four weeks, replaced immediately with a new ring) which is a way to avoid the
oestrogen-withdrawal symptoms experienced by perimenopausal women while maintaining contraceptive efficacy.55,56
In the literature, studies comparing the ring and COCs showed fewer reports of nausea, acne, irritability and
depression in ring users, but more complaints of vaginitis and genital itching.24 On the other hand, with regard to
uterine bleeding patterns, there are conflicting data: some studies report less abundant cycles and spotting with the ring,
while others do not. Concerning the cardiovascular risk, not enough events of TVE, stroke or MI have been found to
assess the differential risk in comparison to COCs.57
This system has the important pros of a better vaginal lubrication thanks to local oestrogen which is very important in
this life stage in which many women begin to suffer from vulvovaginal atrophy: 98% of women showed good lubrication
after just 3 cycles of treatment. This is associated with a favourable impact on vaginal flora (increase in lactobacilli) and
a perfect cycle control, superimposable/superior to that of a COC containing EE 30 µg.58

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Transdermal Patch
The contraceptive patch is, like the vaginal ring, a type of CHC that does not demand daily attention: it is applied to the
skin and worn for 7 days to suppress ovulation, after which the patch is replaced on a weekly basis for two further weeks.
The fourth week is patch-free to allow a withdrawal bleeding.
Its use in this age group is infrequent, and there are no definite data on its continued use; as mentioned earlier in
perimenopause, this is preferred to avoid the occurrence of symptoms in the window period. However, according to the
International Medical Eligibility Criteria for Contraceptive Use, there are no contraindications on the use of transdermal
patch in this life stage.19 However, few studies showed that patch users were less likely to experience bleeding and
spotting than COC users but were more likely to report breast discomfort, nausea, vomiting and menstrual pain.24
With regard to cardiovascular risk, there seems to be an increased risk of VTE with the contraceptive patch compared
to COCs in some studies. If we add to the aforementioned absence of long-term safety data, this contraceptive is
definitely not the first line for the perimenopausal woman.59

Progestin-Only Pill (POP)

Progestin-only pills (POPs), are oestrogen-free oral contraceptives containing only synthetic progestins in low doses,
even lower than those of combined pills. Most perimenopausal patients with contraindications to oestrogen-containing
options, including tobacco use, obesity, migraines with aura, long-standing diabetes, hypertension, or a history of venous
thromboembolism (VTE), can safely use POPs. Contraindications to POPs are limited to a personal history of active or
recent (within 5 years) breast cancer. Their mechanism of action involves changes in cervical mucus, endometrial
development, corpus luteum function and tubal motility and sometimes also prevention of ovulation.60,61 Administration
is daily and continuous, without breaks. Most of the commonly used preparations contain LNG (30 µg), norethisterone
(350 µg) and desogestrel (75 µg). The type of progestin that has the greatest efficacy on ovulation inhibition is
desogestrel, which is comparable to that of CHCs.62 With the decline in fertility with age, the traditional POP becomes
increasingly effective in older users.10 A new option for a POP was recently released with a product containing 4 mg of
drospirenone (DRSP): it suppresses ovulation and thickens cervical mucus because of its higher doses of progestin. This
allows more leeway in the dosing schedule and maintains effectiveness, even with a missed or late pill. DRSP has strong
anti-mineralocorticoid and antiandrogenic properties. The anti-mineralocorticoid properties may lower blood pressure
and reduce fluid retention, helping to combat bloating and some of the weight changes observed in perimenopause. The
antiandrogenic properties have been shown to have a better impact on arterial cardiovascular risk.21
The use of DRSP-only pills showed higher rates of scheduled bleedings and amenorrhea rates and much lower rates
of unscheduled intracyclic bleeding/spotting in comparison to continuous desogestrel regimen of POP.20
The use of POPs may be beneficial in this age group because of the lack of association they have with VTE, stroke,
or MI.
The risk of breast cancer in users of POPs is controversial: in some studies, the risk appears to be the same as for
CHCs, while there is no increased risk in others. Nevertheless, if there is also an increase in risk, it remains minimal and
will continue to reduce after the cessation of POPs.61 On the other hand, with regard to its action on bone, there is no
evidence in the literature of a negative effect on BMD.35
In contrast, the impact on bleeding patterns is important: they are altered in 50% of women using this type of
contraceptive. The bleeding rates associated with DRSP-only pill are better than those for the DSG 75 µg POP, which are
reported to be around 20% for scheduled withdrawal bleeding, 60% for unscheduled intracyclic bleeding/spotting and
15% for amenorrhoea.63 Thus, the DRSP-only pill shows higher rates of scheduled bleedings and much lower rates of
unscheduled intracyclic bleeding/spotting. The improved predictability of bleeding with the DRSP-only pill is an
important advantage of this new hormonal contraceptive.

Depot Medroxyprogesterone Acetate (DMPA)

DMPA is an injectable contraceptive whose effects last for three months, and which contains 104–400 mg of medrox­
yprogesterone acetate.5 There are not enough eligible data about its use during perimenopause due to its limited use in

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some countries. DMPA is related to a small loss in bone mineral density that is generally regained after cessation;
however, it could reduce bone density that represents a critical factor that occurs physiologically during the climacteric
period. Therefore, it is not a first-line contraceptive method after the age of 45 years, although there are no formal
contraindications.64 The dose of DMPA is relatively high compared with the progestin doses in other progestin-only and
oestrogen-containing contraceptive methods, with several unique implications for its use. Of the benefits, amenorrhea
rates are higher than other methods – up to 50% at 1 year of use, with the prevalence of amenorrhea further increasing
with ongoing use. The relatively higher dose of progestin prevents clinically significant interactions with medications that
induce liver enzymes and can attenuate the contraceptive efficacy of the implant and COCs. However, a return to fertility
can be delayed by up to an average of 10 months after the last injection in patients who want to become pregnant
after use.

LARCs
LARCs can represent methods based on mechanical inflammatory effects or progestin-only administration, so that they
do not provide any risk of cardiovascular disease or stroke and none of the other risks and contraindications related to
oestrogen use or simple mechanical methods. These include levonorgestrel-releasing intrauterine systems (LNG-IUS),
etonogestrel subdermal implants and copper intrauterine devices (Cu-IUDs).

Cu-IUDs
Cu-IUDs are a non-hormonal contraceptive method that creates an endometrial inflammatory response causing oedema,
an increase in vascular permeability and macrophage infiltration that creates an unfavourable environment for the embryo
implant. The copper ions released in utero are spermicidal. Thanks to its long action (between 5 and 12 years)65 it can be
an ideal contraceptive method during the whole climacteric, especially in women with contraindications to hormone
supplementation.49 No evidence that the Cu-IUDs lose its effectiveness after 10 years of use has been found at this life
stage.66
Another advantage is that Cu-IUDs can provide emergency contraception if the insertion is within 5 days of
unprotected sexual intercourse.67
Contraindications to IUD placement include the following: known or suspected pregnancy, known or suspected pelvic
inflammatory disease, known or suspected pelvic malignancy, or anatomic conditions that prevent proper placement.
IUDs can easily be placed in an office or clinical setting, without the need for anaesthesia in most instances. The
cumulative risk of IUD expulsion is 10% over 3 years of use. Satisfaction and continuation rates associated with the use
of IUDs are significantly higher than those associated with the use of SARCs such as COCs.
Additionally, Felix et al demonstrated a protective effect on the risk of endometrial cancer compared with women
without these devices.68 However, their use is not recommended in women with heavy menstrual bleeding or dysmenor­
rhea, because copper intrauterine devices can accentuate these two problems; the bleeding patterns can also occur in
women without abnormal endometrial bleeding, but these are not harmful and decrease overtime.7 As we can see, Cu-
IUDs do not act on climacteric symptoms and cannot be used in women with a dysmorphic uterus or known pelvic
inflammatory disease, or in women with submucous fibroids distorting the uterine cavity.7 Finally, when introducing
a Cu-IUD, the woman has to be aware of the risks (very rare) of the procedure, including uterine perforation (2/1000),
infections in the first 20 days (<1/300) and dislocation (5%).49

Implant
Various types of subdermal implants are available worldwide with the 68 mg etonogestrel (Nexplanon® or Implanon
NXT®) being the most common. It is a subdermal implant which releases etonogestrel only and it has to be inserted and
removed by trained operators and in a specific body area, which is 8–10 cm above the medial epicondyle of humerus. It
has a contraceptive efficacy higher than tubal sterilisation with a Pearl index = 0.05/100 women-years. Its pharmaco­
kinetics are such that there is a peak of 220 pg/mL of etonogestrel within the first 4 days after its implantation, which is
greatly higher than the minimum dose needed to inhibit ovulation (90 pg/mL).69 By stopping the ovarian activity, ESI can
act on endometriosis and other conditions affected by hormonal changes.70 The only real discomfort caused by ESI is the

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unpredictability of the bleeding pattern71: for this reason, 15% of women require its removal, as demonstrated by a US
study;72 other reviews count prolonged/frequent bleeding in approximately one in five women.73 There are no associa­
tions with the loss of bone density or metabolic effect74, and it is recommended in obese women as well.75 To underline
these data, women with BMI >30 kg/m2 generally do not require its removal72 and have an optimal hormonal
distribution, unlike other contraceptive methods in which metabolism is highly influenced by weight. ESIs have to be
replaced 3 years after implantation and, unlike IUDs, there are no recommendations to retain them for longer during the
perimenopausal period.74 There is no specific action on the endometrium, so it appears that implants do not protect
against endometrial hyperplasia and breast cancer is a contraindication to its use.49 Based on the aspects discussed here,
the perfect phenotype for ESI in climacteric includes women with BMI > 30 kg/m2 and metabolic diseases or with
a contraindication to oestrogen use.

LNG-IUS (Levonorgestrel-Releasing Intrauterine System)

This is an intrauterine device that releases levonorgestrel only; it is available in three different dosages (13.5 mg, 19.5 mg
and 52 mg), all of them approved for contraceptive use throughout reproductive life. However, only the one which
contains 52 mg of LNG has proven its effectiveness as an endometrial protection if estrogen replacement therapy is
provided.76 LNG-IUS insertion has few contraindications and lots of benefits during climacteric and, if inserted after 45
years, it can be retained for up to seven years in women with menstrual disorders or until menopause if amenorrhoeic
(off-label).49 Within those 7 years, LNG-IUS 52 mg safely prevents pregnancy (contraceptive failure rates are 0.1%
per year in typical use): as a matter of fact, it causes endometrial suppression and increases cervical mucus.6 The IUS has
one of the lowest failure rates of all contraceptive options (0.1% typical and perfect use failure rate).
LNG-IUS has been demonstrated to be the most effective method against abnormal uterine bleeding (AUB) thanks to
its ability to decrease endometrial growth and prostaglandin ratio by promoting the formation of arachidonic acid in the
endometrium.6 LNG-IUS is a safe and effective option in women in perimenopause suffering from heavy bleeding
caused by benign lesions in the uterus or dysmenorrhea.77 In another study, the efficacy of LNG-IUS was compared with
medroxyprogesterone acetate and continuous oral progestin assumption, with the evidence of the supremacy of the first
method in reducing heavy menstrual bleeding in perimenopausal women.78 Therefore, LNG-IUS 52 mg has to be
considered the first-line method in reducing excessive bleeding in women in their forties, considering that amenorrhoea is
expected in up to 45% of women within 6 months of insertion and in up to 50% of women within one year.79
Perimenopausal patients with HMB experience reductions in menstrual bleeding similar to endometrial ablation, often
precluding the need for surgery.80
As stated before, the risk of endometrial cancer increases during perimenopause and the rate of endometrial
hyperplasia consequently rises. LNG-IUS has showed a concrete efficacy in reducing typical endometrial hyperplasia,
so it is recommended in recent guidelines to be the first-line method in this treatment. A study conducted by Abu Hashim
et al81 showed endometrial atrophy after 24 months of LNG-IUS insertion in 100% of women with a documented typical
endometrial hyperplasia.6
The treatment with LNG-IUS 52 mg has also been used in the case of hyperplasia with atypia (endometrial
intraepithelial neoplasia), and it has been associated with its significant regression (moderate-quality evidence) compared
with no treatment.82
Moreover, few studies of its use also in the case of early-stage endometrial cancer stage I A1 in women who want to
preserve fertility have been published, with or without an associated systemic progestin therapy, but its feasibility/
effectiveness has to be clearly demonstrated.
LNG-IUS combined with progesterone ameliorates endometrial thickness and pregnancy outcomes of patients with
early-stage endometrial cancer or atypical hyperplasia.83,84
Another indication to LNG-IUS 52 mg use is the presence of symptomatic fibroids, unless they are submucosal, because
they could cause difficulties in the insertion of LNG-IUS due to endometrial inhomogeneity.6 Generally, myomas tends to
reduce in menopause, but there are cases in which they provoke abnormal bleeding difficult to control; in addition, fibroids
induce aromatase expression, determining the production of inflammatory markers in the endometrium.85 In those cases, the
use of LNG-IUSs should be taken into account. In a study regarding the use of LNG-IUS in perimenopausal women with

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uterine fibroids, hysterectomy was avoided in 89.5% of women after 24 months of LNG-IUS 52 mg insertion.86 Finally,
some oncologists consider the use of LNG-IUS in women using tamoxifen to prevent endometrial hyperplasia.87
Some authors have explored the association between an increase in body weight compared with other contraceptive
methods. It turns out that the increase in body mass index (BMI) with LNG-IUS was higher than in the control group but
lower than with the desogestrel-only pill.88 There is a concern that LNG-IUS can increase the risk of breast cancer: there
are contrasting data regarding these topics, as some articles have proven the association between LNG-IUS and breast
cancer, while others report the opposite.51 Thus, further research is needed to establish whether there is a real connection
with breast cancer risk. Currently, UK Medical Eligibility Criteria for Contraceptive Use state that the risk of LNG-IUS
use in women with active breast cancer is in category 4 (unacceptable risk), whereas the risk is in category 3 (risk
outweigh benefits) for those women who have experienced breast cancer in the past 5 years with no active disease.49
There is no contraindication for patients considered to be at high-risk of breast cancer (eg, family history of breast cancer
or BRCA1/2 mutation carriers).
Moreover, LNG-IUS 52 mg has been well studied in combination with oestrogens and is approved for use as HT
outside of the United States.89,90,91 Although the IUS has contraceptive efficacy for longer than 5 years, it may not
provide adequate endometrial protection from hyperplasia after this time, particularly the IUS with the lower doses
IUS.76 Therefore, women using a lower dose of IUS should be counselled with regard to changing the device earlier to
ensure adequate endometrial protection while using HT.
Ultimately, it seems that LNG-IUS can be associated with important mood changes in a smaller group of vulnerable
women92 (made worse by the climacteric period itself), so that they require antidepressants and have a higher risk of
hospitalisation for depression.93

Irreversible Contraception - Sterilisation

Permanent sterilisation, either via vasectomy of the patient’s partner or tubal ligation/salpingectomy (to further prevent
ovarian cancer) is another possible option in this life stage. These are highly effective methods with 0.5% failure rates or
lower. Patients should be counselled that these are not reversible and are considered permanent solutions. Since there are
currently even more effective and long-acting reversible methods of contraception, the use of this contraceptive method
should increasingly decrease and be selected only in particular situations because it still requires surgery with the associated
recovery costs and risks and it is still associated with a possible negative long-term impact on the ovarian reserve.94

When to Stop Contraception?

Menopause is confirmed with 12 months of amenorrhea in women ages 40 and older according to The North American
Menopause Society (NAMS), while guidelines from The Faculty of Sexual and Reproductive Healthcare (FSRH)
recommend two years of amenorrhea for women between 40 and 50 years old and one year of amenorrhea for those
aged 50 years old or above.7 Continue contraception therapy until menopause is recommended. NAMS further states that
90% of women will reach menopause by age 55 and recommends continuing contraception until mid-50s.95
If a nonhormonal contraceptive method (eg, Cu-IUD) is being used, the above amenorrhea criteria are applicable.
In the case of hormonal contraceptive use, assessing menopausal status is more challenging as amenorrhea may be
artificial. Although hormonal testing is not definitive, Expert Opinion suggests that combining FSH levels with age can
assist with assessing menopausal status in women using hormonal contraceptives between the ages of 50 and 55 years old.96
Most women (95.9%) are menopausal by the age of 55 years and virtually all are menopausal by the age of 59 years.
For women using POP, implant or LNG-IUS, clinicians can check FSH levels once; if it is more than 30 IU/l, the
method can be continued for one more year and then stopped (Figure 1). If the level is less than 30 IU/l, the method
should be continued for another year before rechecking FSH again.97,98 These methods can also be stopped at the age of
55 years without any hormonal evaluation (Figure 3A).96
For women using DMPA, FSH levels are not always impacted. In perimenopausal women, if FSH is suppressed, the
levels generally return to the normal baseline prior to the next injection. For women aged 50–55 years, FSH can be
checked on the day of injection and repeated 13 weeks later prior to the next injection. If both levels are more than 30 IU/
l, contraception can be discontinued (Figure 3B).65,99

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between 50-55 years old

Implant LNG-IUS POP

F S H ……… > 30 IU/L

Continue for 1 more year then STOP

DMPA Injections between 50-55 years old

1st sample: the day of injection 2nd sample: the day of next injection, at least 90 days later

F S H ……… > 30 IU/L F S H ……… > 30 IU/L

The woman can stop immediately

between 50-55 years old

COC Vaginal ring Patch

Stop the method for 6 weeks, if no menses occur:
Stop immediately
1st OPTION

1st sample: after 6 weeks 2nd sample: 1-2 months apart

F S H ……… > 30 IU/L F S H ……… > 30 IU/L

Stop immediately

After 7-14 of hormone free interval:

2nd OPTION

1st sample: after 7-14 days of hormone free interval 2nd sample: 6-8 weeks apart

F S H ……… > 30 IU/L F S H ……… > 30 IU/L

Figure 3 When to stop contraception? In the case of progestin-only pill, implant and levonorgestrel-realising intrauterine system use (A), depot medroxyprogesterone
acetate use (B) and combined hormonal contraceptive (pill, vaginal ring and patch) use (C).

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CHCs users have a more challenging scenario as FSH is more suppressed by the method. For FSRH, they should be
switched to an alternative method at 50 years old (progestin-only, Cu-IUD, etc.) and then follow its specific recommen­
dation. Another option for women aged 50 years and older is to stop their CHCs and use a non-hormonal method for
a while. If they do not resume their menses after 6 weeks, they can check their FSH levels twice, 1–2 months apart; if the
levels are more than 30 IU/l both times, the contraception can be stopped.100 A second option is to check FSH levels at
the end of the 7-day placebo week twice, 6–8 weeks apart. If the FSH level is more than 30 IU/l both times, contraception
can be discontinued (Figure 3C).
False-negative results can occur after 7 days and may require a full 14-day hormone-free interval or longer to repeat
the testing if the woman is able to use a reliable back-up method. For women on CHC, NAMS state that they may
continue CHC until 55 years old if no contraindications exist (Figure 1).95
Once a woman discontinues CHC, she may experience the onset of menopausal symptoms, including vasomotor
symptoms, sleep disturbances, vaginal and urinary tract symptoms and changes in sexual function. At this time,
postmenopausal HT may be considered on an individual basis.

Acknowledgment
No particular acknowledgments for this invited review.

Disclosure
Giovanni Grandi received honoraria for sponsored lectures and participation in advisory boards from Bayer AG,
Italfarmaco, Theramex, Organon, Gedeon Richter and Exeltis, not related to this manuscript. Fabio Facchinetti reports
personal fees from JnJ outside the submitted work. The authors report no other potential conflicts of interest in relation to
this work.

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DOI: 10.1002/ijgo.15446

SPECIAL ARTICLE

FIGO Preconception Checklist: Preconception care for mother

and baby

Chiara Benedetto1,2 | Fulvio Borella1 | Hema Divakar2 | Sarah L. O'Riordan3,4 |

Martina Mazzoli1 | Mark Hanson5 | Sharleen O'Reilly3 | Bo Jacobsson6,7,8,9 |
Jeanne A. Conry10 | Fionnuala M. McAuliffe3,4 | FIGO Committee on Well Woman
Healthcare, FIGO Committee on the Impact of Pregnancy on Long-­Term Health

1
Department of Obstetrics and Gynecology,
Sant'Anna University Hospital, Torino, Italy Abstract
2
FIGO Committee on Well Woman Health The preconception period is a unique and opportunistic time in a woman's life when
Care, London, UK
3
she is motivated to adopt healthy behaviors that will benefit her and her child, making
UCD Perinatal Research Centre, National
Maternity Hospital, University College this time period a critical “window of opportunity” to improve short-­and long-­term
Dublin, Dublin, Ireland health. Improving preconception health can ultimately improve both fetal and ma-
4
FIGO Committee on the Impact of
ternal outcomes. Promoting health before conception has several beneficial effects,
Pregnancy on Long-­Term Health,
London, UK including an increase in seeking antenatal care and a reduction in neonatal mortal-
5
Institute of Developmental Sciences, ity. Preconception health is a broad concept that encompasses the management of
University of Southampton, Southampton,
UK chronic diseases, including optimal nutrition, adequate consumption of folic acid, con-
6
FIGO Division of Maternal and Newborn trol of body weight, adoption of healthy lifestyles, and receipt of appropriate vaccina-
Health, London, UK
tions. Use of the FIGO Preconception Checklist, which includes the key elements of
7
Department of Genes and Environment,
Norwegian Institute of Public Health,
optimal preconception care, will empower women and their healthcare providers to
Oslo, Norway better prepare women and their families for pregnancy.
8
Department of Obstetrics and
Gynecology, Sahlgrenska Academy, KEYWORDS
University of Gothenburg, Gothenburg, lifecourse, nutrition, pregnancy, pregnancy planning, prepregnancy counseling, vaccines
Sweden
9
Department of Obstetrics and
Gynecology, Sahlgrenska University
Hospital, University of Gothenburg,
Gothenburg, Sweden
10
The Environmental Health Leadership
Foundation, California, USA

Correspondence
Fionnuala M. McAuliffe, UCD Perinatal
Research Centre, National Maternity
Hospital, University College Dublin,
Dublin, Ireland.
Email: [Link]@[Link]

The members of the FIGO Committee on Well Woman Health Care and the FIGO Committee on the Impact of Pregnancy on Long-­Term Health, 2021–2023, are listed in Appendix.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction
in any medium, provided the original work is properly cited and is not used for commercial purposes.
© 2024 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology
and Obstetrics.

Int J Gynecol Obstet. 2024;00:1–8.  [Link]/journal/ijgo | 1

 |

18793479, 0, Downloaded from [Link] by Cochrane Mexico, Wiley Online Library on [06/03/2024]. See the Terms and Conditions ([Link] on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2 BENEDETTO et al.

1 | BAC KG RO U N D USA. After adjusting for multiple potential confounders, any pre-
conception care was associated with a modestly decreased risk of
Maternal and fetal mortality and morbidity remain a significant severe maternal morbidity (adjusted odds ratio [aOR] 0.97; 95% CI,
global health issue and are still unacceptably high.1-­3 Every day in 0.95–1.00). However, in a subgroup analysis of women with chronic
2020, almost 800 women died from preventable causes related diseases, such as hypertension, diabetes, or chronic kidney disease,
to pregnancy and childbirth, with a global maternal mortality rate any preconception care was associated with a significant decrease
of 223 per 100 000 live births. Nearly 95% of all maternal deaths in the odds of severe maternal morbidity (aOR, 0.84; 95% CI, 0.77–
occurred in low-­and lower-­middle-­income countries, and most of 0.91). 3 Preconception disorders, such as cardiovascular or mental
1
these deaths could have been prevented. diseases, diabetes, obesity, anemia, and HIV infection, when aggra-
Reducing maternal mortality is the first target of the Sustainable vated by pregnancy, can also become indirect causes of maternal
Development Goal on health and well-­being,4 aimed at reducing the mortality. 8 Moreover, these disorders can affect embryonic devel-
global average maternal mortality rate to below 70 per 100 000 live opment with long-­term consequences for the next generation, per-
births by 2030.1,4 The second target is that of ending preventable petrating the intergenerational cycle of noncommunicable diseases
deaths of newborns and children under 5 years of age, with all coun- (NCDs).9 Therefore, all these disorders should be assessed, man-
tries aiming to decrease neonatal mortality rates to at least as low as aged, and followed up as part of preconception care.10 For exam-
4
12 per 1000 live births. ple, in women with pregestational diabetes mellitus, preconception
In this context, preconception care plays a pivotal role in pre- care can reduce the risk of perinatal mortality by 54% (relative risk
vention. Indeed, in 2013 the WHO developed a global consensus [RR] 0.46; 95% CI, 0.30–0.73).11
on preconception care to reduce maternal and childhood mortality Contraceptive care, as well as gynecologic examinations, were
and morbidity, recognizing its contribution to improving maternal– also associated with a decrease in severe maternal morbidity
fetal outcomes, in both high-­and low-­income countries. 5 (aOR, 0.84; 95% CI, 0.75–0.95 and aOR, 0.79; 95% CI, 0.71–0.88,
Preconception care is defined as: The provision of biomedical, be- respectively).3
havioral, and social health interventions to women and couples before The preconception period is a unique and opportunistic time in
conception occurs. It aims to improve their health status and reduce be- a woman's life when she is motivated to adopt healthy behaviors
haviors and individual and environmental factors that contribute to poor that may potentially benefit her child, making this time period a
maternal and child health outcomes. Its ultimate aim is to improve ma- critical “window of opportunity” to improve pregnancy outcomes.
ternal and child health, in both the short and long term.6 It involves, as a Improving preconception health can ultimately improve both fetal
first step, a comprehensive assessment of those medical, social, and and maternal outcomes.12 Promoting health before conception has
lifestyle factors that may affect a woman's health during pregnancy, been reported to have several beneficial effects, including a 39%
6
as well as that of her child. increase in seeking antenatal care and a 17% reduction in neonatal
It has been estimated that, in the 75 high-­b urden Countdown mortality (RR 0.83; 95% CI, 0.72–0.95).13
Countries, which together account for more than 95% of maternal, Preconception health is a broad concept that encompasses the
neonatal, and child deaths, increasing the coverage and quality of management of chronic diseases, including correct nutrition, ade-
several interventions, including preconception care, could avert quate consumption of folic acid, control of body weight, healthy life-
71% of neonatal deaths (1.9 million; range 1.6–2.1 million), 33% styles, and vaccinations.14
of stillbirths (0.82 million; range 0.60–0.93 million), and 54% of However, given that approximately 50% of pregnancies
maternal deaths (0.16 million; range 0.14–0.17 million) per year around the globe are unplanned, true preconception health care
by 2025.7 requires routine access to “Well Woman Health Care”, which in-
Indeed, preconception care is part and parcel of the “Well cludes the professional asking—whatever the reason for the visit—
Woman Health Care” vision, aimed at preventing illness and promot- one key question: “Are you interested in conceiving this year?”.
ing wellness for girls and women across the globe. If the answer is no, the woman should be offered contraception
advice.
If the answer is yes, then all key factors included in the FIGO
2 | I M PAC T O F PR ECO N C E P TI O N Preconception Checklist should be addressed, including nutrition
C A R E O N M ATE R N A L–FE TA L H E A LTH and weight management, which are all part of the “Well Woman
A N D N O N CO M M U N I C A B LE D I S E A S E S : Health Care” strategy.15 The Preconception Checklist is available
S H O RT-­ A N D LO N G -­T E R M E FFEC T S in downloadable, printable format in the Supporting Information
to this article (Figure FIGO Preconception Checklist).
The association between preconception care, defined as the re- Many women do not see a healthcare professional before preg-
ceipt of specific healthcare services in the 12 months before nancy, therefore the postnatal period also offers an opportunity to
conception, and the risk of severe maternal morbidity including advise on optimal health in preparation for a next pregnancy, should
maternal death, was examined among 1 514 759 women in the it occur, and for women's long-­term health.
 |

18793479, 0, Downloaded from [Link] by Cochrane Mexico, Wiley Online Library on [06/03/2024]. See the Terms and Conditions ([Link] on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
BENEDETTO et al. 3

3 | PR ECO N C E P TI O N C H EC K LI S T: K E Y Obesity
FAC TO R S TO B E A D D R E S S E D
Obesity is the most common medical condition affecting women of
3.1 | Pre-­existing chronic medical conditions reproductive age. Around half of all women in this age group are
either overweight or obese. 21 Excessive obesity increases the risk of
Preconception care in women with chronic medical conditions NCDs, including type 2 diabetes and cardiovascular disease, which
has been associated with an increased likelihood of adopting contribute to over 70% of global deaths annually. 22
healthy behavior, such as medication adherence, folic acid intake, Moreover, obese women are at risk of vitamin D deficiency due
and smoking cessation; quiescent disease during pregnancy; and to the vitamin sequestration in adipose tissue.15 Obesity is an in-
better pregnancy outcomes including reduced congenital anoma- dependent risk factor in pregnancy, with a higher chance of having
lies, obstetric complications, and rates of preterm birth and low pregnancy-­associated hypertension, insulin-­dependent gestational
birthweight.10 diabetes, and infants with macrosomia. Excessive gestational weight
Therefore, preconception care is essential for potentially gain and postpartum weight retention may play a significant role
high-­risk women during pregnancy owing to pre-­existing medical in long-­term obesity. Having one child doubles the 5-­and 10-­year
conditions such as metabolic, cardiovascular, neurological, auto- obesity incidence for women, with many women who gain excessive
immune, and/or endocrine diseases. In such cases, preconception weight during pregnancy remaining obese permanently. 23 Therefore,
care should focus on attaining disease quiescence during the peri- excessive gestational weight gain and/or postpartum weight reten-
conception period, adjusting medications to those appropriate for tion should be considered as they significantly contribute to short-­
pregnancy before conception, as well as verifying compliance with and long-­term adverse health outcomes for mother, baby, and future
them. Moreover, general healthy behaviors should be promoted, pregnancies. 24 Women with a BMI of more than 30 should be re-
including those aimed at limiting exposure to pollutants and toxic ferred to a dietician.
10,15
chemicals.

Underweight
3.2 | Nutrition
Low maternal weight and BMI at conception or delivery, as well as
Maternal nutrition at conception affects placental development and poor weight gain during pregnancy, are associated with low birth-
function, as well as fetal genomic imprinting/programming and, con- weight, prematurity, and maternal delivery complications. 25–28
16,17
sequently, the child's long-­term health. Micronutrient deficiencies, such as low folate, iron, and/or vita-
However, a thorough review of the dietary intakes of nutrients in min B12, may lead to anemia and its associated adverse pregnancy
adolescent girls and women of reproductive age in low-­and middle-­ outcomes. 27 It is recommended that all women are screened for ane-
income countries reported that dietary deficiencies such as low iron, mia in the preconception period.15 Women with severe underweight
vitamin A, iodine, and zinc and/or calcium, remain prevalent despite should be referred to a dietician.
18
the reduction in underweight mothers. In high-­income countries,
a typical diet that includes a high intake of red meat, refined grains/
sugars, and high-­fat dairy products is also lacking in several import- 3.3 | Supplementation
ant micronutrients, such as magnesium, iodine, calcium, and vitamin
D.19 Folic acid
To address these issues, FIGO developed a simple Nutrition
Checklist that includes questions on specific dietary requirements, Early use of folic acid prevents neural tube defects (NTDs).
body mass index (BMI), diet quality, and micronutrients. Answering Adequate levels of folate in pregnancy, measured as a red blood cell
these questions raises awareness, identifies potential risks, and folate concentration above 906 nmol/L, can be difficult to achieve
collects information that can inform health-­promoting conversa- through diet alone, therefore women of reproductive age should
tions between women and their healthcare professionals. The FIGO be prescribed folic acid both during the preconception period and
Nutrition Checklist is free to download at: [Link] ww.​figo.​org/​ throughout pregnancy. NTDs occur due to the neural tube failing
news/​figo-­​nutri​tion-­​check​list. A digital version ([Link] to close at approximately 3–4 weeks of gestation and may lead to
org/c/​kuxayx3e) is also available, which gives individualized feed- infant mortality or long-­term disability. 29 Although the proportion of
back based on answers. This checklist has been validated for use NTDs that can be prevented by sufficient folate intake has not yet
across many healthcare settings. This allows wider access through been established, the general consensus is that it is probably about
mobile phones or other electronic devices, as mobile health tech- 50%–60%.30 Randomized controlled trials have reported significant
nologies offer information that is well accepted by women and par- reductions in the prevalence rates of NTDs with adequate folic acid
ticularly beneficial for those who have low socioeconomic status, a supplementation.31 Indeed, in low-­
resource countries, the intro-
20
young age, and/or a high BMI. duction of periconceptional folic acid supplementation has been
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4 BENEDETTO et al.

demonstrated to reduce the incidence of NTDs (RR 0.53; 95% CI, Stopping smoking is associated with improved pregnancy and
0.41–0.77; two studies, n = 248 056), whilst iron–folic acid supple- child health outcomes, including reductions in the incidence of low
mentation reduced the rates of anemia (RR 0.66; 95% CI, 0.53–0.81; birthweight, preterm birth, intensive care unit admissions, and peri-
six studies; n = 3430), particularly when supplemented weekly and natal mortality.43
32
in a school setting. Therefore, as cigarette smoking is one of the most import-
Moreover, a study of over 1.5 million women demonstrated ant modifiable risk factors associated with adverse perinatal out-
that folic acid supplementation, taken 3 months before pregnancy, comes, smoking cessation advice should be given to women before
was associated with a significantly lower risk of low birthweight, pregnancy.
miscarriage, stillbirth, and neonatal mortality, compared with no
use. 33
WHO recommends routine daily folic acid dosing for low-­risk Alcohol consumption
women at a dose of 0.4 mg per day, starting 3 months before concep-
tion.34 Those at increased risk of NTDs, including women with a BMI Alcohol use during pregnancy is a leading preventable cause of birth
of more than 30, a history of an NTD in a previous child, epilepsy or defects and developmental disabilities, with fetal alcohol syndrome
anticonvulsant use, and/or pre-­existing type 2 diabetes, require a (FAS) being one of the most severe outcomes. Other adverse health
higher folic acid dose of 4–5 mg per day.35 effects associated with alcohol use in pregnancy include miscar-
riage, preterm labor, intrauterine growth restriction, and stillbirth,
which all add morbidity to any potential underlying disability.44,45
Other micronutrients Moreover, consuming alcohol during pregnancy may lead to neu-
ropsychological adverse outcomes in the newborn.44,45 Regardless,
A significant number of women of reproductive age, especially the alcohol use in pregnancy remains common, with a global prevalence
youngest, do not meet even the minimum recommended levels of approximately 10%, with rates of use varying depending on the
of certain nutrients in their diet (known as the reference nutrient country where the woman resides.46 In fact, the global prevalence
intake), in particular mineral intake. For instance, 77% of women of FAS in children and youths in the general population has been
aged 18–25 years were found to have insufficient daily dietary estimated to be 7.7 per 1000 population.47
intakes of iodine and 96% of women of reproductive age had Women should be advised to avoid drinking alcohol if they are
daily intakes of iron and folate below the recommended levels for planning a pregnancy. Currently, literature reports no recommended
pregnancy.19 safe level of alcohol consumption during pregnancy. Therefore, pre-
Preconception supplementation of certain micronutrients is as- conception counseling should include addressing this issue prior to
sociated with a reduction in several adverse obstetric outcomes, for pregnancy.
example calcium and vitamin D supplementation reduce the risk of
pre-­eclampsia36; myoinositol, probiotics, and micronutrient supple-
mentation decrease the risk of preterm births (aRR 0.43; 95% CI, Substance use
37
0.22–0.82). Moreover, preconceptional micronutrient supplemen-
tation may influence intellectual development in offspring. In fact, Women are at the greatest risk of developing a substance use dis-
preconception supplementation with multiple micronutrients has order in their reproductive years, with the highest prevalence rates
been found to improve certain domains of intellectual functioning observed in adolescence and early adulthood.48 The use of illicit
in offspring at 6–7 years of age, compared with folic acid alone.38 drugs in pregnancy is associated with adverse maternal, fetal, and
Therefore, it is crucial to provide information about micronutrient child outcomes, including abortion, neonatal abstinence syndrome,
supplementation during preconception counseling. placental abruption, intrauterine growth restriction, preterm birth,
hemorrhage, as well as fetal and infant mortality. Therefore, women
should be advised to discontinue the use of such substances and
3.4 | Lifestyle variables informed about both short-­and long-­term risks for themselves and
their babies.49
Tobacco smoking cessation

Tobacco use during pregnancy is associated with adverse preg- Exposure to toxic environmental chemicals
nancy outcomes, including miscarriage, ectopic pregnancy, preterm
delivery, fetal growth restriction, small-­
for-­
gestational-­
age, low Links between prenatal exposure to environmental chemicals and
39–42
birthweight, placental abruption, stillbirth, and neonatal death. adverse health outcomes throughout the life course, including nega-
Indeed, smoking during pregnancy may cause impaired placental de- tive impacts on fertility, pregnancy, neurodevelopment, and cancer,
velopment, leading to a hypoxic environment with reduced provision have been documented.50 Some of these chemicals are still widely
41
of oxygen and micronutrients to the fetus. used, such as solvents, pesticides, phthalates, lead, methyl mercury,
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BENEDETTO et al. 5

polycyclic aromatic hydrocarbons, bisphenol A, and per-­and poly- at risk of hyperthermia, dehydration, and excessive weight loss.58
fluorinated substances. They can be found in households and work- These risks need to be discussed with female athletes seeking to
places, in food, water, air, and consumer products. become pregnant.
FIGO considers preventing exposure to environmental chemicals
a priority. This involves giving women timely information on how to
avoid or reduce such exposure.50 Furthermore, the health impacts 3.5 | Vaccines
of toxic environmental chemicals can be exacerbated by climate
change.51,52 Therefore, some advice on protection against the nega- A pregnant woman and her fetus/newborn are vulnerable to severe
tive consequences of climate change should also be provided during infectious diseases. Therefore, determining the immunization status
53
counseling. of every woman in her reproductive years is of pivotal importance,
whatever the reason for her consulting a healthcare professional.
This would make it possible for women to be protected when and if
Physical activity the time comes for a pregnancy.
Vaccination to prevent maternal and perinatal adverse outcomes
Establishing a pattern of regular physical activity prior to pregnancy should be offered against hepatitis B virus, human papilloma virus,
is an important component of healthy pregnancy planning as it has influenza, measles–mumps–rubella (MMR), meningococcal (ACWY
a positive effect on the well-­being of the mother and can contribute and B), varicella, tetanus, diphtheria, and pertussis.60,61
to the prevention of adverse maternal–fetal outcomes.54 However, As there is a theoretical risk to the fetus when the mother is given
a pooled analysis of 358 population-­based surveys with 1.9 million a live virus vaccine, women should be counseled to avoid becoming
participants aged over 18 showed a global age-­standardized preva- pregnant for 28 days after having MMR and/or varicella vaccines.
lence of insufficient physical activity of about 32% in females. The Moreover, women who may get pregnant during the influenza sea-
highest prevalence (about 43%) of insufficient physical activity was son should be given inactivated or recombinant influenza vaccines.
observed in women from Latin America, the Caribbean, South Asia,
and high-­income Western countries.55
Prepregnancy risk factors for physical inactivity include a higher 3.6 | Pregnancy intervals
or lower than normal prepregnancy BMI, a lower maternal educa-
tion level, and a history of previous live births.56 Therefore, more Short interpregnancy intervals (<6 months) are associated with pre-
thorough counseling should be offered to patients with these risk term birth, very preterm birth, low birthweight, small-­for-­gestational-­
factors. age, offspring death, neonatal intensive care unit admission, and
Indeed, the presence/absence of knowledge on healthy behav- congenital abnormalities.62 Interpregnancy intervals between 6
iors have been shown to be the most commonly assessed enabler/ and 12 months are also associated with increased rates of preterm
barrier to women's lifestyle behavior change during the preconcep- birth.63 Moreover, the length of the interpregnancy interval is a sig-
57
tion period. nificant contributor to neonatal morbidity, whatever the gestational
The FIGO Pregnancy and Noncommunicable Diseases age at birth. Indeed, both short (<12 months) and long (>24 months)
Committee and the FIGO Committee for Reproductive Medicine, interpregnancy intervals are independently associated with a higher
Endocrinology, and Infertility, as well as the American Society for rate and risk of neonatal morbidity, despite preterm influences, as
Reproductive Medicine and the American College of Obstetricians compared with intervals of between 12 and 24 months.64
and Gynecologists (ACOG), recommend moderate physical activity These data suggest that a time lapse of between 12 and
of at least 30 min a day, 5 days a week, for a minimum of 150 min 24 months between pregnancies is most likely the optimal interval
of moderate exercise per week. These levels of exercise are recom- to minimize perinatal adverse outcomes63 as well as long-­term risks
15,58
mended prepregnancy, during pregnancy, and postpartum, as for maternal health, including all-­cause mortality.65 Furthermore,
several studies report that pregnant women generally do not engage a woman's individual characteristics and outcome of any previous
in much physical activity.54 Association with dietary modifications is birth should also be taken into consideration when counseling on the
related to a greater weight loss than exercise alone.15,58 most adequate interpregnancy interval and appropriate contracep-
Particular attention must be paid to some categories, such as tion,66 aiming at decreasing the risks for both mothers and babies.
professional female athletes. To date, there is a paucity of evidence
as to the effects of their physical activity during pregnancy. A recent
systematic review suggests that there are no known significant neg- 4 | FI G O P OS ITI O N O N PR ECO N C E P TI O N
ative consequences of physical activity for pregnant athletes. This CARE
would imply that pregnant women who engage in higher impact ac-
tivities, including elite and competitive athletes, can approach sports Preconception care is pivotal in improving women's health before
with confidence.59 On the other hand, ACOG suggests caution, stat- conception to prevent short-­and long-­term adverse outcomes for
ing that women performing high levels of physical activity may be both mothers and babies.
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6 BENEDETTO et al.

Indeed, preconception care addresses risk factors and health DATA AVA I L A B I L I T Y S TAT E M E N T
issues that contribute to maternal and perinatal mortality and mor- Data available upon request.
bidity, including pre-­existing chronic medical conditions, harmful
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59. Wieloch N, Klostermann A, Kimmich N, Spörri J, Scherr J. Sport

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62. Wang Y, Zeng C, Chen Y, et al. Short interpregnancy interval can APPENDIX
lead to adverse pregnancy outcomes: a meta-­analysis. Front Med.
Members of the FIGO Committee on Well Woman Health Care,
2022;9:922053.
63. Lengyel CS, Ehrlich S, Iams JD, Muglia LJ, De Franco EA. Effect 2021–2023: Hema Divakar (Chair), Chiara Benedetto (Vice Chair),
of modifiable risk factors on preterm birth: a population based-­ Griselda Quijada, Chin-­Long Chang, Tesfaye Hurissa, Paola Iturralde,
cohort. Matern Child Health J. 2017;21:777-­785. Gelila Goba, Méabh Ní Bhuinneáin, Gulshan Ara, Christine Solbach,
64. DeFranco EA, Seske LM, Greenberg JM, Muglia LJ. Influence of in-
Suvarna Khadilkar, Nyawira Ngayu, Christian Jackisch, Ahmed
terpregnancy interval on neonatal morbidity. Am J Obstet Gynecol.
2015;212(386):e1-­e9. Fawzy Galal, Elizabeth Pumpure, Diana Ramos.
65. Weisband YL, Manor O, Friedlander Y, Hochner H, Paltiel O, Members of the FIGO Committee on Impact of Pregnancy on
Calderon-­Margalit R. Interpregnancy and interbirth intervals and Long-­Term Health, 2021–2023: Fionnuala McAuliffe (Chair), Liona
all-­
c ause, cardiovascular-­related and cancer-­ related maternal
Poon (Vice Chair), Graeme Smith, Virna Medina, Sumaiya Adam, Pat
mortality: findings from a large population-­based cohort study. J
Epidemiol Community Health. 2020;74:957-­963. O'Brien, Moshe Hod, Esraa Algurjia, Lina Bergman, David McIntyre,
66. Mühlrad H, Björkegren E, Haraldson P, Bohm-­Starke N, Kopp Kallner Anil Kapur, Ronald Ma, Mary Rosser, Cynthia Maxwell, Claudio Sosa,
H, Brismar WS. Interpregnancy interval and maternal and neonatal Valerie Guinto, Titus Beyuo, Francisco Ruiloba.
morbidity: a nationwide cohort study. Sci Rep. 2022;18(12):17402.

S U P P O R T I N G I N FO R M AT I O N
Additional supporting information can be found online in the
Supporting Information section at the end of this article.
Journal Pre-proof

UNIVERSAL ACCESS TO CONTRACEPTION: WOMEN, FAMILIES, AND

COMMUNITIES BENEFIT

Laurel W. Rice, MD, Eve Espey, MD, MPH, Dee Fenner, MD, Kimberly D. Gregory,
MD, Ms. Jacquelyn Askins, Charles J. Lockwood, MD, MHCM

PII: S0002-9378(19)31121-4
DOI: [Link]
Reference: YMOB 12885

To appear in: American Journal of Obstetrics and Gynecology

Received Date: 12 July 2019

Revised Date: 27 August 2019
Accepted Date: 12 September 2019

Please cite this article as: Rice LW, Espey E, Fenner D, Gregory KD, Jacquelyn Askins M, Lockwood
CJ, UNIVERSAL ACCESS TO CONTRACEPTION: WOMEN, FAMILIES, AND COMMUNITIES
BENEFIT, American Journal of Obstetrics and Gynecology (2019), doi: [Link]
[Link].2019.09.014.

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1 UNIVERSAL ACCESS TO CONTRACEPTION: WOMEN, FAMILIES, AND

2 COMMUNITIES BENEFIT

5 Laurel W. RICE, MD1, Eve ESPEY, MD, MPH2, Dee FENNER, MD3, Kimberly D.
6 GREGORY, MD4, Ms. Jacquelyn ASKINS1, Charles J. LOCKWOOD, MD, MHCM5
7
1
8 University of Wisconsin-Madison; Madison, WI; Department of Obstetrics and Gynecology
2
9 University of New Mexico School of Medicine; Albuquerque, NM; Department of Obstetrics
10 and Gynecology
3
11 University of Michigan; Ann Arbor, MI; Department of Obstetrics and Gynecology
4
12 Cedars-Sinai Medical Center; Los Angeles, CA; Department of Obstetrics and Gynecology
5
13 University of South Florida; Tampa, FL
14

15 Corresponding Author:
16 Laurel W. Rice, MD
17 lwrice@[Link]
18 University of Wisconsin-Madison, School of Medicine and Public Health
19 McConnell Hall, 4th Floor
20 1010 Mound Street
21 Madison, WI 53715
22 608-417-4213
23

24 Conflicts of Interests:
25 There are no conflicts of interest to report.
26

27 Word count: 1914

28 Abstract word count: 154

29

30

1
31 CONDENSATION
32 This report reviews why contraception must be readily available to ALL women, improving their

33 lives as well as that of their families and society.

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55 ABSTRACT (WITH KEY WORDS)

56 Universal access to contraception benefits society: unintended pregnancies, maternal mortality,

57 preterm birth, abortions, and obesity, would be reduced by increasing access to affordable

58 contraception. Women should be able to choose when and whether to use contraception, what

59 method to use and have ready access to their chosen method. State and national government

60 should support unrestricted access to all contraceptives. As obstetrician-gynecologists, we have

61 a critical mandate, based on principle and mission, to step up with leadership on this vital

62 medical and public health issue, to improve the lives of women, their families, and society. The

63 field of Obstetrics and Gynecology must provide the leadership for moving forward. The

64 American Gynecological and Obstetrical Society (AGOS), representing academic and public

65 policy leaders from across all disciplines of Obstetrics and Gynecology, is well-positioned to

66 serve as a unifying organization, focused on developing a strong unified advocacy voice to fight

67 for accessible contraception for all in the U.S.

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73

74 Key Words: Contraception, Unintended Pregnancies, Maternal Mortality, Preterm Birth,

75 Abortions, Obesity, Affordability, Access, Advocacy

76

77

3
 78 INTRODUCTION:

79 Contraception is a fundamental component of health care that improves wellness, protects

80 against a variety of adverse health conditions, prevents unplanned pregnancies, empowers

81 women to reach their full potential, and has a positive impact on families, communities, and

82 society. Contraceptive use has substantially contributed to women’s societal advancement,

83 enabling growing numbers of women to obtain college education, pursue advanced professional

84 degrees, and join the paid workforce.1 In recognition of the full impact of contraception, in 2011

85 the National Academy of Medicine (formerly the Institute of Medicine) recommended

86 contraception as a key preventive health service, paving the way for the contraceptive mandate

87 of the Affordable Care Act (ACA). The latter required insurance companies to cover FDA-

88 approved contraceptives with no cost sharing.

89

90 In late 2018, the Trump administration issued two rules providing employers more flexibility to

91 deny women insurance coverage for birth control.2 The first provided exemption from the

92 contraceptive coverage mandate to entities that object to such coverage based on religious

93 beliefs. The second rule provided exemption to nonprofit organizations and small businesses that

94 may have non-religious moral objections to such coverage. While a U.S. District judge issued a

95 nationwide preliminary injunction against this new policy in January 2019, the case continues to

96 make its way through the courts. The Trump administration also proposed that any organization

97 that provides or refers patients for abortions be ineligible for Title X funding, which covers a

98 range of other vital women’s health services including sexually transmitted disease prevention,

99 cancer screenings, and contraception; such restrictions will have dire consequences for women’s

100 health. The 9th US Circuit Court of Appeals upheld the Trump administration’s interpretation of

4
101 the federal Title X statute, allowing the domestic gag rule to go into effect.3 Legal challenges

102 continue; the ultimate implementation of these rules will likely be determined by the Supreme

103 Court.

104

105 The American Society of Gynecology and Obstetrics (AGOS) is an academic society of

106 obstetrician-gynecologists; as multidisciplinary experts in women’s health care and based on

107 overwhelming evidence, we advocate for full unrestricted access to contraception. Our focus is

108 on access, understanding the importance of a reproductive-justice based approach to

109 contraception counseling and provision. Women should have free choice about whether and

110 when to use contraceptives as well as the choice of contraception. Non-directive non-coercive

111 counseling is key to honoring women’s choices about their contraceptive method use or non-use.

112 Access to contraception should not be restricted by the government and should be universally

113 covered by private and public payers. Increased access to affordable contraception reduces

114 unintended pregnancies, maternal mortality, preterm birth, abortions, and obesity and improves

115 the health of women, families and communities.

116

117 UNINTENDED PREGNANCY:

118 In the U.S., approximately half of pregnancies are unintended, with about 48% of reproductive

119 age women experiencing at least one unintended pregnancy.4 Providing women with readily

120 accessible and affordable contraception is the most effective way to reduce the rate of unintended

121 pregnancy, and, pari passu, reduce the occurrence of abortion5. It will also improve health and

122 economic issues facing women. Beginning in 2009, the privately-funded Colorado Family

5
123 Planning Initiative (CFPI) supported provider training and financing for the provision of long-

124 acting reversible contraceptive (LARC) methods at Title X funded clinics.6 As a consequence,

125 by 2011 LARC use among 15- to 24-year-olds grew from 5% to 19%. Compared with expected

126 fertility rates in 2011, observed rates were 29% lower among low-income 15- to 19-year-olds

127 and 14% lower among low-income 20- to 24-year-olds. In participating Colorado counties, the

128 proportion of high-risk births fell 24%, and abortion rates fell 34% and 18%, respectively,

129 among women aged 15 to19 and 20 to 24. This case study provides compelling support for

130 enhanced access to affordable contraception and further evidence that programs that increase

131 LARC access among young, low income women decrease unintended pregnancies.

132

133 MATERNAL MORTALITY:

134 Over the past three decades, the world has seen a steady decline in the number of women dying

135 in childbirth. Unfortunately, the U.S., unlike other high-income countries, is a notable outlier,

136 with maternal mortality continuing to climb.7 We currently spend nearly 18% of our gross

137 domestic product (GDP) on health care, which is high compared with health care spending in ten

138 other high-income countries, including 9.6% (Australia) and 12.4% (Switzerland). IIn 2013, the

139 U.S. ranked 60th in the world in maternal mortality.8 Maternal mortality rates have risen steadily

140 from 7.2 pregnancy-associated deaths per 100,000 births in 1987 to 17.3 deaths per 100,000 in

141 2013.9 Some of this increase can be ascribed to improved surveillance, and in fact, accurate

142 assessment of maternal deaths is critically important as the first step in addressing root causes.

143

144 The five leading causes of maternal mortality include cardiovascular disease, other medical

145 conditions, infection/sepsis, hemorrhage, and cardiomyopathy.9 Many of these conditions—

6
146 especially those related to the cardiovascular system—can be optimized during the

147 preconception or interconception period, underscoring the need for enhanced access to affordable

148 contraception during this period. Further data suggest that short interpregnancy intervals (<18

149 months) are associated with increased risk of adverse maternal outcomes; with women over 35

150 years of age at particularly high risk.10 Enhanced access to, and use of, contraceptives would not

151 only reduce the 45% of pregnancies in the U.S. that are unintended but could reduce maternal

152 mortality by nearly 30%.11

153

154 PREMATURITY:

155 In 2018, for the fourth year in a row, U.S. preterm birth rates—already among the highest in the

156 developed world—rose again to 10.02%.12 The risk of spontaneous preterm birth increases four-

157 fold among women whose interval between a prior delivery and the last menstrual period

158 preceding their next pregnancy is ≤ 6 months.13 A cohort study of over 112,000 women who

159 were seen at least once by a provider within 18 months of delivery reported that for every month

160 of contraceptive coverage, the risk of preterm birth decreased by 1.1%.14 Furthermore, women

161 with a short interpregnancy interval (<18 months) have an increased risk of small for gestational

162 age infants and increased risk of fetal demise.10 Providing contraception, including long-acting

163 reversible contraception (LARC), in the immediate postpartum period has been shown to

164 increase contraceptive use at six and 12 months. This maternal health-oriented intervention to

165 lengthen interpregnancy intervals may be among our most effective strategies to stem the

166 epidemic of preterm births and associated infant mortality and the long-term adverse health

167 consequences that accrue to affected infants.15

168

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169 PREVENTING ABORTIONS:

170 The primary determinant of the abortion rate is the unintended pregnancy rate. Unintended

171 pregnancies frequently result from lack of access to contraception due to various impediments

172 including financial barriers, inadequate health care access, lack of reproductive health providers,

173 religious prohibitions, and personal factors such as fear, embarrassment, and lack of knowledge.

174 The population-level association between access to contraception and abortion rates has been

175 convincingly demonstrated in several studies. The Contraceptive CHOICE study simulated the

176 no-cost sharing element of the ACA contraceptive mandate, enrolling nearly 10,000 women in

177 St. Louis, MO. Women who enrolled obtained scripted counseling and their choice of

178 contraceptive method at no cost. A substantial reduction in the abortion rate occurred in the

179 CHOICE cohort compared to a similar population without the intervention of scripted counseling

180 and no-cost contraception.16 The contraceptive mandate has played a major role in improving

181 access to contraception nationally, which has correlated with an associated decline in abortions.17

182

183 Despite strong evidence demonstrating the critical role of contraception in reducing the abortion

184 rate, efforts have already weakened the ACA’s contraceptive mandate. Another pillar of

185 contraceptive access has been similarly compromised: Title X has ensured access to

186 contraception for low-income women since 1970. New regulations severely undermine the

187 program’s success and run counter to the National Academy of Medicine’s quality principles.

188 Under proposed regulations, Title X providers will be restricted from offering evidence-based

189 contraception care and reproductive health counseling. Instead of a focus on expanding access to

190 contraception, a number of current state-level attempts to reduce abortions have focused on

191 restricting or banning abortion access. In countries where abortion is illegal or highly restricted,

8
192 abortion rates are similar to those of countries where abortion is broadly legal, demonstrating

193 that restricting abortion access is an ineffective strategy to reduce the abortion rate18.

194 Additionally, most abortion-related deaths occur in countries where abortion is illegal or highly

195 restricted18. With weakening of the contraceptive mandate and restrictions to Title X, access to

196 contraception is shrinking at a time when expanded access is most needed to empower women,

197 through non-coercive counseling, to make their own reproductive health decisions which may

198 result in reduced unintended pregnancy and abortion and improve overall maternal, infant, and

199 family health.19

200

201 OBESITY:

202 Obesity in pregnancy may have major health impacts. For women with obesity who decide on

203 contraception use, universal access could reduce the number of pregnancies and increase inter-

204 pregnancy intervals with a lifelong health impact. Obesity is the most common medical

205 condition in women of reproductive age. Obesity during pregnancy has short term and long term

206 adverse consequences for women. At term, the risk of cesarean delivery, endometritis, and

207 wound complications is increased in obese women. Moreover, late pregnancy complications

208 including gestational diabetes and preeclampsia, both of which are associated with long-

209 term morbidities, are also increased in obese women.20 Postpartum, obese women have an

210 increased risk of venous thromboembolism and a higher risk of pulmonary embolism,

211 depression, and difficulty with breast-feeding.21

212

213 A total of 50-60% of overweight or obese women gain more weight during pregnancy than

214 recommended by National Academy of Medicine gestational weight guidelines leading to

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215 postpartum weight retention. Additional weight increases future cardiometabolic risks and pre-

216 pregnancy obesity in subsequent pregnancies. For women who wish to use contraception,

217 avoiding unintended pregnancy reduces this incremental weight gain.22 Short inter-pregnancy

218 intervals are associated with increased risk of subsequent pre-pregnancy obesity and gestational

219 diabetes.23 Efforts to improve nutrition and physical activity during pregnancy and after delivery

220 require not only a concerted effort on the part of the individuals, but potentially considerable

221 fiscal resources and commitments of time. Populations at greatest risk often have the least

222 resources and the greatest socioeconomic burden. Hence, obesity during pregnancy needs to be

223 recognized as not only an individual problem but also as a major public health threat.20 Access

224 to safe, effective contraception enables obese women at risk for life-threatening co-morbidities

225 during and after pregnancy to maximize their health prior to conception.

226

227 SUMMARY:

228

229 According to the World Health Organization, “The health of women and girls is of particular

230 concern because in many societies they are disadvantaged by discrimination rooted in

231 sociocultural factors.”24 In the U.S., the legalization of birth control access and introduction of

232 federal family planning programs have had measurable impacts on women’s lives. In 1999, the

233 Centers for Disease Control and Prevention reported on family planning as one of the ten great

234 public health achievements of the 20th century, noting that family planning altered the social and

235 economic roles of women as well as allowing women to have desired smaller family sizes and

236 desired increased inter-pregnancy intervals that improved outcomes for newborns and reduced

237 maternal mortality24.

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238

239 Contraception must be available, affordable, and accessible to all who seek it. This health

240 enhancing intervention alone would improve the lives of millions of women around the globe,

241 including the U.S., as well as their families and society at large. High quality women’s health

242 care demands that patients’ health be placed above politics. As women’s health experts, we

243 advocate for evidence-based strategies to optimize health including universal unrestricted access

244 to contraception. The American Gynecological and Obstetrical Society (AGOS), representing

245 academic and public policy leaders from across multiple disciplines of Obstetrics and

246 Gynecology, is a committed member of the advocacy coalition to address this vitally important

247 issue.

248

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257

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259

260

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261 REFERENCES:

262 1. Bailey MJ, Reexamining the impact of family planning programs on US fertility: evidence from

263 the War on Poverty and the early years of Title X, American Economic Journal: Applied

264 Economics, 2012, 4(2):62–97

265 2. Fact Sheet: Final Rules on Religious and Moral Exemptions and Accommodation for

266 Coverage of Certain Preventive Services Under the Affordable Care Act. [Link].

267 [Link]

268 moral-exemptions-and-accommodation-for-coverage-of-certain-preventive-services-

269 [Link]. Published November 7, 2018.

270 3. Reuters. Trump Abortion Referral ‘Gag Rule’ Survives Demands for Emergency Halt.

271 The New York Times. July 11, 2019.

272 [Link]

273 [Link]. Accessed 7/12/19.

274 4. Finer L, Zolna M. Declines in Unintended Pregnancy in the United States, 2008–2011.

275 New Engl J Med. 2016; 374(9):843-852. doi:10.1056/nejmsa1506575.

276 5. MMWR Surveill Summ. 2018 Nov 23; 66(25): 1–44.

277 Published online 2018 Nov 23. doi: 10.15585/mmwr.ss6625a1

278 6. Ricketts S, Klingler G, Schwalberg R. Game Change in Colorado: Widespread Use Of

279 Long-Acting Reversible Contraceptives and Rapid Decline in Births Among Young,

280 Low-Income Women. Perspect Sex Reprod Health. 2014;46(3):125-132.

281 7. Kassebaum N, Barber R, Bhutta Z et al. Global, regional, and national levels of maternal

282 mortality, 1990–2015: a systematic analysis for the Global Burden of Disease Study

283 2015. The Lancet. 2016;388(10053):1775-1812. doi:10.1016/s0140-6736(16)31470-2.

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284 8. Kassebaum N, Bertozzi-Villa A, Coggeshall M et al. Global, regional, and national levels

285 and causes of maternal mortality during 1990–2013: a systematic analysis for the Global

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292 Interval With Pregnancy Outcomes According to Maternal Age. JAMA Intern Med.

293 2018;178(12):1661. doi:10.1001/jamainternmed.2018.4696

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295 analysis of 172 countries. Lancet. 2012 Jul 14;380(9837):111-25. doi: 10.1016/S0140-

296 6736(12)60478-4. Epub 2012 Jul 10. PMID: 22784531.

297 12. Hamilton BE, Martin JA, Osterman MJK, Rossen LM. Births: Provisional data for 2018.

298 Vital Statistics Rapid Release; no 7. Hyattsville, MD: National Center for Health

299 Statistics. May 2019.

300 13. Behrman RE, Butler AS. Preterm Birth: Causes, Consequences, and Prevention.

301 Washington, D.C.: National Academies Press; 2007.

302 14. Rodriguez MI, Chang R, Thiel de Bocanegra H. The impact of postpartum contraception

303 on reducing preterm birth: findings from California. Am J Obstet Gynecol. 2015 Nov;

304 213(5):703.e1-6. doi: 10.1016/[Link].2015.07.033. Epub 2015 Jul 26. PMID: 26220110

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309 10.1016/[Link].2016.10.015. Epub 2016 Oct [Link]: 27806833.

310 16. Peipert JF, Madden T, Allsworth JE, et al. Preventing unintended pregnancies by

311 providing no-cost contraception. Obstet Gynecol 2012;120:1291–7.

312 17. Mulligan, K. Contraception Use, Abortions, and Births: The Effect of Insurance

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314 18. Singh S, Remez L, Sedgh Gilda, et al. Abortion Worldwide 2017: Uneven Progress and
315 Unequal Access, New York: Guttmacher Institute.

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321 20. Catalano PM, Shankar K. Obesity and pregnancy: mechanisms of short term and long

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329 23. Hutcheon JA, Nelson HD, Moskosky S et al. Short interpregnancy intervals and adverse

330 maternal outcomes in high-resource settings: An updated systematic review. Paedatr

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332 24. Women's health. World Health Organization.

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339

340

15
Original Research

Method of Hormonal Contraception and

Protective Effects Against Ectopic Pregnancy
Helena Kopp-Kallner, PhD, Marie Linder, PhD, Carolyn E. Cesta, PhD, Silvia Segovia Chacón, RNM, MSc,
Helle Kieler, PhD, and Sofie Graner, PhD

OBJECTIVE: To estimate the incidence rates for ectopic defined as having at least two records of International Clas-
pregnancy by contraceptive method in a cohort of women sification of Diseases, Tenth Revision code O00-, including
using hormonal contraception in Sweden between 2005 O00.0, O00.1, O00.2, O00.8, O00.9, within 30 days or one
and 2016. episode of O00- and one surgical procedure for ectopic
METHOD: Women aged 15–49 years with a filled prescrip- pregnancy (NOMESCO Classification of Surgical Proce-
tion for a hormonal contraceptive in the Swedish Pre- dures code LBA, LBC, LBD, LBE, LBW). Incidence rates
scribed Drug Register between 2005 and 2016 were per 1,000 woman-years and 95% CIs were calculated for
included. For each woman, all exposed woman-years were each method of contraception.
allocated to treatment episodes depending on the method RESULTS: The study included 1,663,242 women and 1,915
of contraception. Treatment time started on the day the events of ectopic pregnancy. The incidence rate (95% CI)
prescription was filled and ended on the first day of the for ectopic pregnancy per method of hormonal contracep-
end of supply, new eligible dispensing, pregnancy-related tion was estimated: 13.5-mg levonorgestrel (LNG) hor-
diagnosis and its associated estimated last menstrual monal intrauterine device (IUD), 2.76 (2.26–3.35) per 1,000
period, or removal procedure. Ectopic pregnancy was woman-years; 52-mg LNG hormonal IUD, 0.30 (0.28–0.33)
per 1,000 woman-years; combined oral contraception, 0.20
(0.19–0.22) per 1,000 woman-years; progestogen implants,
From the Department of Clinical Sciences, Danderyd Hospital, Karolinska
Institute, the Department of Obstetrics and Gynaecology, Danderyd Hospital,
0.31 (0.26–0.37) per 1,000 woman-years; oral medium-dose
Karolinska Institutet, Clinical Epidemiology Division/Centre for Pharmacoepi- progestogen (desogestrel 75 mg), 0.24 per 1,000 woman-
demiology, Karolinska Hospital, the Department of Laboratory Medicine, years, (0.21–0.27); and oral low-dose progestogen (norethis-
Karolinska Institute, and BB Stockholm, Danderyds Hospital, Stockholm,
Sweden.
terone 0.35 mg and lynestrenol 0.5 mg), 0.81 (0.70–0.93) per
1,000 woman-years.
Supported by the Karolinska Institute, Sweden. The funding source had no
influence on or access to the results before publication of the manuscript. CONCLUSION: Hormonal contraception lowers the risk
Each author has confirmed compliance with the journal’s requirements for of ectopic pregnancy markedly. The incidence rate of
authorship. ectopic pregnancy among women using a low-dose hor-
Corresponding author: Sofie Graner, PhD, Karolinska Institutet, Clinical monal IUD (13.5 mg LNG) was substantially higher than that
Epidemiology Division/Centre for Pharmacoepidemiology, Karolinska Hospital, in women using other types of hormonal contraception.
Stockholm, Sweden; email: [Link]@[Link].
This study provides real-world evidence to inform best clin-
Financial Disclosure
ical practice for women-centered contraceptive counseling.
Marie Linder, Carolyn E. Cesta, Silvia Segovia Chacón, and Helle Kieler are
employees of the Centre for Pharmacoepidemiology, Karolinska Institutet, which (Obstet Gynecol 2022;139:764–70)
receives grants from several entities (pharmaceutical companies, regulatory DOI: 10.1097/AOG.0000000000004726
authorities, and contract research organizations), including Bayer, for perfor-

E
mance of drug safety and drug utilization studies. Helena Kopp-Kallner reports
personal fees outside the submitted work from Bayer for contracted work as ctopic pregnancy is a major cause of maternal mor-
lecturer and serving on advisory boards and institutional fees as principal inves- bidity and mortality globally, accounting for approx-
tigator for trials for Bayer outside the submitted work. The other authors did not imately 4% of the maternal mortality in the United
report any potential conflicts of interest.
Kingdom.1 Ectopic pregnancy also causes significant
© 2022 The Author(s). Published by Wolters Kluwer Health, Inc. This is an
open access article distributed under the terms of the Creative Commons morbidity in the form of surgical procedures, medica-
Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), tion with methotrexate, and reduced fertility, which may
where it is permissible to download and share the work provided it is properly result in subsequent need for assisted reproductive tech-
cited. The work cannot be changed in any way or used commercially without
permission from the journal. nology.2–4 Approximately 2% of all pregnancies are
ISSN: 0029-7844/22 ectopic.5 In Sweden, where the current study took place,

764 VOL. 139, NO. 5, MAY 2022 OBSTETRICS & GYNECOLOGY

the average incidence rate of ectopic pregnancy from tion of Sweden is approximately 10 million, and the
2008 to 2016 was approximately 0.83 cases per 1,000 Swedish government has given consent for each
woman-years for ages 15–49 years.6 The incidence has individual’s data to be included. All registers include
increased in the past decade, and contraception failure the civil registration number of each resident, a
has been discussed as one plausible factor contributing unique number assigned at birth or immigration that
to the increase.7 In 2019, 49% of all women of repro- allows linkage of individual data between regis-
ductive age (15–49 years) worldwide were using some ters.19,20 We obtained linked data from three national
form of contraception.8 registers: the Prescribed Drug Register, the National
It is estimated that approximately 450 million Patient Register, and the Medical Birth Register. The
women use hormonal or intrauterine contraception Medical Birth Register includes maternal data such as
daily worldwide.9 Hormonal contraception may be parity, the date of the last menstrual period, and preg-
either a combination of estrogen and a progestogen nancy outcomes including date of birth of the neo-
(pills, patches, or vaginal rings) or progestogen only nate. The Prescribed Drug Register includes data on
(pills, intrauterine devices [IUDs], implants, or injec- dispensed substances, dispensed dose, package sizes,
tions). The most effective protection from experienc- and formulations according to the Anatomical Thera-
ing an ectopic pregnancy is to use a modern peutic Chemical (ATC) Classification System, includ-
contraceptive method and, thereby, reduce risk of ing the date of dispensation, from July 1, 2005.20 The
unintended pregnancy. Long‐acting reversible contra- National Patient Register includes all in-patient admis-
ception, including hormonal IUDs, are user indepen- sions and outpatients visits to the Swedish hospitals,
dent with a low risk of unintended pregnancy and, in and their associated diagnosis according to the Inter-
Sweden, are often favored by young nulliparous national Classification of Diseases, Tenth Revision
women.10–13 However, if pregnancy occurs, approxi- (ICD-10) codes.
mately 25–50% of these pregnancies are ectopic preg- In a Swedish setting, most women receive con-
nancies.14 The risk of ectopic pregnancy with use of traceptive counseling by midwives at booked appoint-
other hormonal contraception is less studied.13,15–17 ments or during drop-in visits at maternity health
There are studies indicating that progestogen-only clinics. Most contraceptive counseling and prescrip-
hormonal contraception is associated with an tion is performed by midwives within the public
increased risk of ectopic pregnancy.16 Currently, health system and free of charge. All medication,
there are three types of hormonal IUDs available on including hormonal contraception, is free of charge
the European market (including Sweden), containing for women aged 18 years or younger. For women up
13.5, 19.5, and 52 mg of levonorgestrel (LNG). The to 26 years of age, contraception is subsidized.
hormonal IUD with 13.5 mg LNG with a smaller Hormonal contraception requires a prescription.
insertion tube was introduced in Sweden in 2014. Removal of long-acting reversible contraceptives is
After its introduction, use of hormonal IUDs in nul- performed free of charge by a midwife at patient
liparous women increased significantly. The hor- request. Women who choose to have contraceptive
monal IUD with the lowest dose has been reported counseling, prescription, insertion, or removal per-
in a small study (N51,040 women) to be associated formed by a medical doctor pay a fee for the visit.
with a higher risk of ectopic pregnancy when com- In Sweden, all suspected cases of ectopic preg-
pared with the 52-mg LNG hormonal IUD.18 In nancy are routinely referred by any health care
2017, new text about the risk of ectopic pregnancy professional to hospital care because of the need for
was included in the summary of products rapid follow-up, repeated serum human chorionic
characteristics. gonadotropin testing, and assessment for surgical or
The aim of this population-based national register medical (methotrexate) treatment.
study was to estimate the incidence rate for ectopic All women in Sweden registered in the Prescribed
pregnancy by contraceptive method in a cohort of Drug Register with a filled prescription of a hormonal
women aged 15–49 years using hormonal contracep- contraceptive (ATC code G02B or G03A), excluding
tion in Sweden between 2005 and 2016. spermicides (ATC code G02BB) and emergency
contraceptive pills (ATC code G03AD01 or
METHODS G03AD02), between July 1, 2005, and December
Sweden has population-based national registers, 31, 2016, were included in the study population.
which include information for all inhabitants on Eligible dates were all dates with filled prescriptions
demographic and health indicators such as births, of a unique ATC code, excluding dates with filling of
dispensed drugs, and hospital contacts. The popula- two or more different contraceptives. The date of the

VOL. 139, NO. 5, MAY 2022 Kopp-Kallner et al Hormonal Contraception and Risk of Ectopic Pregnancy 765
first filled eligible prescription during the study period were tabulated. Incidence rates by contraceptive
was defined as the index date. Women older than age method and by risk factor were calculated with 95%
50 years and women who had undergone a steriliza- confidence limits using Byar’s method. A sensitivity
tion procedure before the index date were excluded analysis excluding treatment episodes with a history
from the source population. All women were followed of ectopic pregnancy was performed.
from the index date until their 50th birthday, steriliza- A Cox regression model adjusted for age, history
tion, death, emigration, or the administrative end of of endometriosis, previous ectopic pregnancy, and
the study data linkage (December 31, 2016). contraceptive class was fitted to time to ectopic
For each woman, all exposed woman-years were pregnancy, assuming proportional hazards between
allocated to treatment episodes, depending on the levels within each covariate. The analytic unit was
method of contraception: hormonal IUDs containing treatment episodes, allowing each woman to contrib-
13.5 mg (ATC code G02BA) or 52 mg LNG (ATC ute more than once and to more than one contracep-
code G02BA), combined hormonal contraceptives tive method. The fitted model was used for prediction
(patches ATC code G03AA13, vaginal rings ATC (as opposed to those observed directly in the data) of
code G02BB0, and pills ATC codes G03AA and survival probabilities and was presented as graphs of
G03AB), etonogestrel implants (ATC code 1-P compared with survival time in years for each
G03AC08), oral medium-dose progestogen-only (des- specific combination of age, history of endometriosis,
ogestrel 75 mg, ATC code G03AC09), oral low-dose and previous ectopic pregnancy covering the 13.5-mg
progestogen-only (norethisterone 0.35 mg and lynes- LNG hormonal IUD and the three most common
trenol 0.5 mg, ATC code G03AC01-02), and me- hormonal contraceptive methods (52-mg LNG hor-
droxyprogesterone acetate injections (ATC code monal IUD, combined oral contraception, and oral
G03AC06). Unexposed time was not included. medium-dose progestogen-only contraception). Ethi-
The length of treatment time started at dispensing cal permission for the study was granted by the
date and ended on the first day of end of supply, new regional ethical committee in Stockholm (diary num-
eligible dispensing, pregnancy related diagnosis and ber 2014/1884-31).
its associated estimated last menstrual period, or
removal procedure (for IUDs or implants). Individual RESULTS
dispensings were summed into treatment episodes by The study population included a total of 1,663,242
adding the treatment time for each dispensing with a women who contributed a total of 6,807,293 treat-
maximum gap of seven days (grace period) between ment episodes, which totalled 6,960,110 woman-
stop of the current dispensing and start of next years. Figure 1 describes the study population flow
dispensing of the same contraceptive agent. Women chart. The study participants had a mean age of 27
could reenter the cohort with a new dispensing of a years, and the majority (64%) were nulliparous at the
prescription. inclusion in the cohort. Table 1 describes the baseline
Ectopic pregnancy was defined as at least two characteristics of the participants at the index date.
records of ectopic pregnancy (ICD-10 code O00-, Combined oral contraception contributed the most
including O00.0, O00.1, O00.2, O00.8, O00.9) within woman-years (40.1%) in the cohort, followed by the
30 days or one record of ectopic pregnancy and a 52-mg LNG hormonal IUD (24.7%). Table 2 shows
procedure code for surgery for ectopic pregnancy the total prescriptions and associated number of
(NOMESCO Classification of Surgical Procedures woman-years per contraceptive method.
code LBA, LBC, LBD, LBE, LBW) during the same There were 1,915 ectopic pregnancies during the
treatment episode. Within the 30-day window, the study period resulting in an incidence rate of 0.28 per
first fulfilled definition of ectopic pregnancy was used 1,000 woman-years (95% CI 0.26–0.29). Among
as the date for the outcome. women with a history of endometriosis, the incidence
The survival curves were adjusted for the identi- rate was 0.25 (95% CI 0.12–0.44) per 1,000 woman-
fied available confounders age (younger than 40 years and was 6.09 (95% CI 4.88–7.50) per 1,000
years, 40 years or older), diagnosis of endometriosis woman-years for women with a history of ectopic
(ICD-10 code N80, yes or no), and previous ectopic pregnancies. No woman in the study had both a his-
pregnancy (defined as above, yes or no). tory of previous ectopic pregnancy and endometriosis
Baseline characteristics of the study population at time of inclusion in the cohort.
were expressed as numbers and proportions. The The 13.5-mg LNG hormonal IUD was used by
number of events (ectopic pregnancies) and woman- 2.3% of the study population, of whom 104 had an
years for each contraceptive method and risk factor ectopic pregnancy (incidence rate 2.76 per 1,000

766 Kopp-Kallner et al Hormonal Contraception and Risk of Ectopic Pregnancy OBSTETRICS & GYNECOLOGY
 rates per method of hormonal contraception in detail.
The sensitivity analysis excluding treatment episodes
with a history of ectopic pregnancy (0.3%) decreased
the incidence rates by 0.01–0.03 (data not shown).
The Cox regression models adjusted for history
of ectopic pregnancy and endometriosis and strati-
fied by age group are presented in Appendix 1,
available online at [Link]
C638, showing the relatively higher predicted risk
for ectopic pregnancy in women with a history of
ectopic pregnancy independent of method of hor-
monal contraception. The highest predicted risk for
Fig. 1. Population flow chart. ectopic pregnancy was seen in women younger than
Kopp-Kallner. Hormonal Contraception and Risk of Ectopic Preg- age 40 years with a previous history of ectopic
nancy. Obstet Gynecol 2022.
pregnancy using the 13.5-mg LNG IUD. According
to the model, approximately nine cases of ectopic
woman-years, 95% CI 2.26–3.35). The hormonal 52- pregnancy in 100 treatments are expected for the
mg LNG IUD was used by 26.1% of the study pop- 13.5-mg LNG IUD during 2.5–3 years of use in this
ulation, of whom 522 had an ectopic pregnancy (inci- specific subset of the study population.
dence rate 0.30 per 1,000 woman-year, 95% CI 0.28–
0.33). Table 2 and Figure 2 describe the incidence DISCUSSION
In this large, population-based prospective cohort
Table 1. Baseline Characteristics of Women in the study among women of reproductive age using
Study Population at the Time of the First hormonal contraception, the risk of ectopic pregnancy
Contraceptive Dispensing, July 1, 2005– was highest among the women using 13.5-mg LNG
December 31, 2016 (N51,663,242) hormonal IUDs (2.76 per 1,000 woman-years) com-
pared with all other methods of hormonal contracep-
Characteristic Value tion, which had similar highly protective rates. The
results support the findings from a hospital-based
Age (y) 27.069.9
Younger than 15 59,368 (3.6) study in which low-dose hormonal IUDs were asso-
15–19 513,146 (30.9) ciated with lower protective effects compared with
20–29 481,773 (29.0) higher-dose hormonal IUDs.18
30–39 376,020 (22.6) The overall incidence rate of ectopic pregnancy
40–50 232,935 (14.0)
Highest level of education
in the study population was low, 0.28 per 1,000
Elementary school 402,134 (24.2) woman-years from 2005 to 2016, as compared with
High school 544,385 (32.7) the average approximate incidence rate of 0.83 per
College or university 418,262 (25.2) 1,000 woman-years for those aged 15–49 years in the
Postgraduate 5,257 (0.3) Swedish population between 2008 and 2016.6 This
Missing 293,204 (17.6)
suggests that all the hormonal contraceptives effec-
Parity
0 1,059,003 (63.7) tively prevented pregnancies to varying degrees and
1 15,404 (9.3) subsequently lowered the absolute risk of ectopic
2 or more 448,835 (27.0) pregnancy. The current study supports previous find-
Country of birth ings that progestogen-only methods may be associ-
Sweden 1,421,169 (85.5)
ated with a lesser protective effect than combined
Nordic countries except Sweden 27,361 (1.7)
EU except the Nordic countries 43,223 (2.6) methods.16 This may be explained by the fact that
Europe except EU and Nordic countries 35,340 (2.1) many women continue to ovulate during use of hor-
Asia 86,558 (5.2) monal IUDs and oral low-dose progestogen-only pills.
Other 48,962 (2.9) When adjusting the results for previous ectopic
Missing 629 (0.0)
pregnancy or endometriosis, the effect of age is clearly
Medical history
Previous ectopic pregnancy 36 (0.0) demonstrated, with women younger than age 40 years
Endometriosis 11,675 (0.7) having a higher predicted relative risk of ectopic
EU, European Union. pregnancy independent of the use of hormonal
Data are mean6SD or n (%). contraception. This is expected because of their

VOL. 139, NO. 5, MAY 2022 Kopp-Kallner et al Hormonal Contraception and Risk of Ectopic Pregnancy 767
Table 2. Number of Treatment Episodes, Ectopic Pregnancies, and Woman-Years Per Hormonal
Contraceptive Method, Sweden, 2005–2016

Proportion of
No. of Median No. of Total IR/1,000
Type of Hormonal No. of Treatment Follow- Ectopic Woman- Woman- Woman-
Contraception Women Episodes up (y) Pregnancies Years Years (%) Years 95% CL

Any contraceptive 1,663,242 6,807,293 0.5 1,915 6,960,110 0.28 0.26–0.29

Hormonal IUD
13.5 mg LNG 37,539 37,731 0.87 104 37,647 0.5 2.76 2.26–3.35
52 mg LNG 434,242 523,391 3.27 522 1,719,652 24.7 0.30 0.28–0.33
Combined hormonal
contraception
Vaginal 154,265 405,432 0.29 54 206,875 3.0 0.26 0.20–0.34
Patch 40,320 77,176 0.34 20 40,979 0.6 0.49 0.30–0.75
Oral 973,704 2,932,214 0.62 566 2,790,107 40.1 0.20 0.19–0.22
Etonogestrel implant 188,257 251,232 2.16 149 479,066 6.9 0.31 0.26–0.37
Progestogen-only
contraception
Medium-dose (oral, 657,078 1,783,618 0.42 286 1,181,276 17.0 0.24 0.21–0.27
desogestrel 75
mg)
Low-dose (oral, 150,597 394,696 0.46 198 245,180 3.5 0.81 0.70–0.93
norethisterone
0.35 mg and
lynestrenol 0.5
mg)
Medroxyprogesterone 91,800 401,803 0.36 16 259,327 3.7 0.06 0.04–0.10
acetate injection
By age (y)
Younger than 40 1,430,307 5,752,697 0.50 1,834 5,709,869 0.32 0.31–0.34
40 or older 384,403 1,054,596 0.53 81 1,250,240 0.06 0.05–0.08
Endometriosis
No 1,651,567 6,762,183 0.50 1,904 6,915,450 0.28 0.26–0.29
Yes 12,715 45,110 0.46 11 44,660 0.25 0.12–0.44
Previous ectopic
pregnancy
No 1,663,206 6,788,680 0.50 1,827 6,945,662 0.26 0.25–0.28
Yes 6,558 18,613 0.43 88 14,448 6.09 4.88–7.50
IR, incidence rate; CL, confidence limit; IUD, intrauterine device; LNG, levonorgestrel.

higher fertility. For all subgroups, the 13.5-mg LNG diagnosis of endometriosis, a common condition,
hormonal IUD was associated with the lowest pro- but the prevalence may be underestimated when
tective effect, most evident for the women with a using diagnosis data from the patient register, because
history of ectopic pregnancy, which has been reported severe cases of endometriosis are predominantly seen
previously.15 in hospitals. Consequently, the effect of endometriosis
The strength of this study is its large population on ectopic pregnancy may be overestimated. The data
size, with prospectively collected data comprising all were not adjusted for other known risk factors of
women in Sweden using hormonal contraception ectopic pregnancy, including history of pelvic inflam-
during the study period, assuring generalizability of matory disease, chlamydia infection, or tubal surgery,
the results and reduced risk of selection or recall bias. because none of these conditions are contraindica-
The Swedish population-based National Patient Reg- tions for the use of any of the hormonal contraceptive
ister contains information on all inpatient and out- methods, including IUD.21,22
patient care in the Swedish hospitals, allowing The limitations of the study include the lack of
information on known risk factors such as history of information on smoking in the Swedish health regis-
ectopic pregnancy or endometriosis to be included. ters. Smoking is a possible contraindication for
The analyses were adjusted for women with a combined oral contraception, especially if the woman

768 Kopp-Kallner et al Hormonal Contraception and Risk of Ectopic Pregnancy OBSTETRICS & GYNECOLOGY
Fig. 2. Crude incidence rates and
95% CIs for ectopic pregnancies per
method of hormonal contraception
and covariates, Sweden 2005–2016
(log scale). Progestogen-only con-
traception medium-dose: desogestrel
75 mg; progestogen-only contracep-
tion low-dose: norethisterone 0.35
mg and lynestrenol 0.5 mg. IUD,
intrauterine device; LNG, levo-
norgestrel.
Kopp-Kallner. Hormonal Contraception
and Risk of Ectopic Pregnancy. Obstet
Gynecol 2022.

is older than age 40 years. This may influence the year duration of its use in the majority of the users. In
results; however, we judge this effect to be minor. a previous study from our research team, the risk of
Other limitations include difficulties confirming the ectopic pregnancy among users of the13.5-mg LNG
actual use of contraception. It is known that early hormonal IUD was highest in the beginning of use.18
discontinuation rates differ between methods of hor- This may indicate a possible overestimation of the risk
monal contraception.23,24 In the current study it is of ectopic pregnancy among users of the 13.5-mg
assumed that the women are currently using the pre- LNG hormonal IUD in the current study. However,
scribed hormonal contraception if they filled a pre- the more than fivefold relative higher incidence rate
scription valid for a certain period and have no of ectopic pregnancy for the 13.5-mg LNG hormonal
record in the registers for indicating otherwise (such IUD is unlikely to be fully explained by this
as a pregnancy related diagnosis, or removal proce- overestimation.
dure for IUD or implant). Records of filled prescrip- These findings are clinically relevant for pro-
tions do not capture actual use. We therefore do not viding real life evidence when providing counseling
know whether or when the dispensed contraception is about methods of contraception to women who wish
used but make the assumption that use, and therefore to preserve fertility. Hormonal IUDs are user-
treatment time, begins on the date of dispensation. friendly and safe to use, providing women with
Hence, the study may underestimate the protective highly effective and reversible long-acting contra-
effect of hormonal contraception on the risk of ectopic ception with few side effects. The results of the
pregnancy. Further, the Prescribed Drug Register current study indicate that the 13.5-mg LNG hor-
does not include treatment without prescription (eg monal IUD should not be recommended for women
drugs given during inpatient care). However, because who are concerned about the risk of ectopic preg-
hormonal contraception is exclusively prescribed as nancy. The 13.5-mg LNG hormonal IUD was
outpatient care, the potential missed treatment epi- marketed to a younger (or primiparous) population
sodes are assumed to be negligible in this study. The owing to its smaller size compared with the 52-mg
risk of missing cases of ectopic pregnancy is assumed LNG hormonal IUD. A hormonal IUD containing
to be small, because all cases of ectopic pregnancy in 19.5 mg LNG and with the same size as the 13.5-mg
Sweden are referred to hospitals for assessment of LNG hormonal IUD was approved for the Swedish
need for surgical or medical treatment and follow- market in November 2016. Hence, it has not been
up. The 13.5-mg LNG IUD has been available on possible to study the product during the current
the market in Sweden since January 2014. Because study period. Further research is needed on the 19.5-
our study period ended in 2016, we could not study mg LNG hormonal IUD and risk of ectopic preg-
the effects on the risk of ectopic pregnancy for the 3- nancy in real-life settings.

VOL. 139, NO. 5, MAY 2022 Kopp-Kallner et al Hormonal Contraception and Risk of Ectopic Pregnancy 769
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770 Kopp-Kallner et al Hormonal Contraception and Risk of Ectopic Pregnancy OBSTETRICS & GYNECOLOGY