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\begin{document}

\title{Hormonal contraception increases the risk of depression -- also in
Sweden}



\author[1]{Ojvind Lidegaard}%
\affil[1]{Rigshospitalet, University of Copenhagen}%


\vspace{-1em}



  
  \date{June 17, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
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\selectlanguage{english}
\begin{abstract}
Background. Recently three large-scale epidemiological registry-based
Scandinavian studies examined the association between use of hormonal
contraception and the risk of developing depression or use of
antidepressants. They reached surprisingly divergent results.

Objectives: The aim of this study was to explain why these three recent
studies from Denmark and Sweden could achieve quite different results,
interpretations, and conclusions.

Methods: Search strategi and selection. The three existing large scale
Scandinavian studies examining associations between exposure to
different types of hormonal contraception and risk of depression or use
of antidepressants were examined according to chosen design, exclusion
criteria, and included confounders. Methodological choices were
considered, and the validity of these methodological choices tested.~

Main results. First, the assumption that differences between studies are
due to residual confounding is proven unlikely, already because
confounder control beyond age, year and education rarely change
estimates materially. More likely basic differences in chosen study
groups, exclusions from the study groups, exposure definitions, chosen
reference populations, and interpretation of the results seem to explain
the differences between the studies.

Conclusion. The detailed review of the three Scandinavian studies
reveals methodological choices as the main explanation for their
different findings. Residual confounding was found unlikely to explain
the divergent results, while ideological circumstances might have a main
responsibility for the different chosen methods and for the
interpretation of the results.

Funding. None.%
\end{abstract}%



\sloppy


16.2.2022

\par\null

\textbf{Hormonal contraception increases the risk of depression}

\textbf{-- also in Sweden}

\selectlanguage{ngerman}\emph{Øjvind Lidegaard\textsuperscript{1}, Professor, DMSci}

ORCID: 0000-0002-7071-5496

Word count abstract: 222 words

Word count main text: 2486 words

Number of tables: 2

Number of figures: 0

Department of Gynaecology, Rigshospitalet, University of Copenhagen,
Denmark

Department of Clinical Medicine, University of Copenhagen, Copenhagen,
Denmark

Correspondence to Professor Øjvind Lidegaard, e-mail:
\href{mailto:Oejvind.Lidegaard@regionh.dk}{\nolinkurl{Oejvind.Lidegaard@regionh.dk}}

\textbf{Abstract}

Background. Recently three large-scale epidemiological registry-based
Scandinavian studies examined the association between use of hormonal
contraception and the risk of developing depression or use of
antidepressants. They reached surprisingly divergent results.

Objectives: The aim of this study was to explain why these three recent
studies from Denmark and Sweden could achieve quite different results,
interpretations, and conclusions.

Methods: Search strategi and selection. The three existing large scale
Scandinavian studies examining associations between exposure to
different types of hormonal contraception and risk of depression or use
of antidepressants were examined according to chosen design, exclusion
criteria, and included confounders. Methodological choices were
considered, and the validity of these methodological choices tested.

Main results. First, the assumption that differences between studies are
due to residual confounding is proven unlikely, already because
confounder control beyond age, year and education rarely change
estimates materially. More likely basic differences in chosen study
groups, exclusions from the study groups, exposure definitions, chosen
reference populations, and interpretation of the results seem to explain
the differences between the studies.

Conclusion. The detailed review of the three Scandinavian studies
reveals methodological choices as the main explanation for their
different findings. Residual confounding was found unlikely to explain
the divergent results, while ideological circumstances might have a main
responsibility for the different chosen methods and for the
interpretation of the results.\emph{\textbf{Funding.} None.}\textbf{Key
words:} hormonal contraception, depression, oral contraceptives,
antidepressant drugs



\textbf{Introduction}

Over recent years, three Nordic large-scale epidemiological studies have
tried to quantify the influence of use of different types of hormonal
contraceptives on the risk of developing depression or use of
antidepressant drugs\textsuperscript{1-3}. In the following, the first
Danish study\textsuperscript{1} is called ``study 1'', the first Swedish
study\textsuperscript{2} ``study 2'', and the second Swedish
study\textsuperscript{3} ``study 3'' according to time of publication.
Although at first sight these three studies seem rather similar in
methods, the authors of these three studies -- surprisingly - made quite
different conclusions from their findings, although some results were
similar in all three studies. Going into details on the methods,
however, may reveal differences which might explain the different
findings and conclusions.

The issue is important, because hormonal contraception (HC) is one of
the most frequent medical exposures worldwide, and depression or use of
antidepressants are among the most frequent outcomes in the same
countries.

The aim of this study was to compare the three studies and explore
whether differences in methods may explain the different results, and
whether ideological differences towards hormonal contraception also may
play a role for the chosen methods and the interpretation of the
results.

\textbf{Design}

All three studies were historical registry-based cohort studies.

\textbf{Material}

The three Scandinavian studies included women 15-34, 12-30 and 15-25
years old, and the study periods 2000-2013, 2010-2011, and 2010-2017,
respectively (Table 1). Study populations were 1.1, 0.8 and 0.7 million,
sufficiently large to assess risk estimates for specific age groups and
specific product groups.

\textbf{Methods}

\emph{Inclusion and exclusion criteria}

Eligible for inclusion in all three studies were women without previous
psychiatric diseases or use of antidepressants or psychotropic drugs
during a four- or five-year period prior to the study period. Pregnant
women were excluded in all three studies. Women with previous thrombosis
or cancer were excluded in study 1 and 3 and controlled for in study 2.
Study 3\textsuperscript{3} in addition excluded all women having used
hormonal contraception before the age of 15 years. The argument was that
women starting use of hormonal contraception before 15 years often have
medical conditions indicating that use. Study 3 also excluded women who
during the study period developed other mental disorders, also if at the
same time getting a depression diagnosis.

\emph{Exposure definition}

All three studies had national prescription registries as source of
their exposure data. Study 1 considered women as exposed to HC if having
a valid prescription within the last six months prior to either use of
antidepressants or getting a depression diagnosis. Study
2\textsuperscript{2} considered a valid prescription of HC as being
exposed. Study 3\textsuperscript{3} considered a valid prescription of
HC within the first four weeks after prescription as non-use, so that
women were considered users of HC from four weeks after starting use of
HC. The argument was that women could not develop a depression or start
use of antidepressants due to use of HC so quickly after starting this
use.

Study 1 and 2 followed women from they started using HC, whereas study 3
examined current users (Table 2).

\emph{Reference group}

All three studies had non-users of HC (previous users + never-users) as
the reference group for the main analysis. Study 1 and 3 also made a
full analysis with never-users as reference, and study 1 in addition an
analysis where each woman was her own control, by comparing the risk of
depression during a period before use, with the period after starting
using HC, thereby eliminating potential unmeasured confounders between
persons if being stable over time (Table 2).

\emph{Outcomes}

Study 1 had antidepressant use and getting a depression diagnosis as
outcomes, each made up separately. Study 2 had psychotropic medication
as outcome, which in addition to antidepressants included anxiolytics,
hypnotics, and sedatives. These four groups were analysed together.
Study 3 had antidepressant or getting a depression diagnosis as
outcomes, analysed together.

\emph{Covariates}

All three studies were controlled for age, socioeconomic status
(educational length or income), different medical conditions such as
endometriosis, polycystic ovary syndrome, adiposity, and smoking. Study
2 additionally adjusted for epilepsy, migraine, premenstrual disorders,
bleeding disturbances, and hospital admissions. Study 3 additionally for
mental disturbances in parents.

\emph{Statistical analysis}

Study 1 and 3 made a Poisson regression analysis. Study 2 a logistic
regression where outcomes among exposed were measured during the first
year after starting exposure, and among non-exposed outcomes during
2011.

\emph{}

\textbf{Results}

The results of the three studies are summarized in Table 1. All three
studies demonstrated:

\begin{itemize}
\tightlist
\item
  An overall significantly increased relative risk of outcomes with use
  of HC (study 3 only with never-users as reference or young age group)
\item
  Higher relative risk (or odds ratio) of outcomes with non-oral
  combined products than with use of combined oral contraceptives.
\item
  Higher relative risk of outcomes in adolescents than in older young
  women.
\item
  Higher relative risk of outcomes with levonorgestrel intrauterine
  system (LNG-IUS) than with use of oral contraceptives.
\item
  Higher relative risk of outcomes when using never-users as reference,
  than when using non-users as reference group (study 1 and 3).
\end{itemize}

Important differences in results between the three studies were also
demonstrated:

\begin{itemize}
\tightlist
\item
  Study 1 and 2 had generally substantially higher relative risk
  estimates for all product groups than study 3.
\item
  Study 1 and 2 demonstrated significantly increased relative risks of
  outcomes for all product groups, whereas study 3 demonstrated
  significantly increased risks with all products groups except use of
  oral contraceptives, which in the main analysis demonstrated a
  significant protection against depression.
\item
  With increasing age, oral contraceptive use implied in study 1 a
  decrease in relative risk of depression from 1.8 to 1.2, in study 2
  from 3.3 to 1.1 and in study 3 from 1.0 to 0.8.
\end{itemize}

\textbf{Discussion}

Most colleagues would probably consider the three included studies as
well conducted, well described, and well reported. Some main
methodological head points should be discussed, however.

Main findings

The analysis demonstrated that small but crucial differences in
exclusion criteria, age groups chosen, and reference population imply
substantial influence on the results achieved. Further that the
methodological choices and interpretation of the results seem to highly
ideologically influenced.

Strengths and limitations

\emph{Exclusions}

Previous studies have demonstrated former depression to be the most
important risk factor for new depressions. Therefore, it is correct
primarily to exclude women with previous depression from such studies.
It makes no sense, however, to disregard the first four weeks of use of
HC and decide to classify this exposure period as non-exposed. Those who
experience mood changes by use of HC often report these symptoms within
days after starting this use, as demonstrated in study 1 and 2 which
followed women from start of HC exposure. That methodological decision
in study 3 will certainly underestimate the real risk of depression
development.

The other main difference between study 1 and 2 versus study 3 was the
exclusion of all women having used HC before turning 15 years. Thereby,
the age groups with the highest sensitivity for depression development
with HC use were excluded. Many of these women would have started use of
antidepressants after turning 15 years, while still being exposed to HC.
Exclusion of this group will thus also underestimate the risk of
depression development.

Finally, women who in addition to a depression also were recorded with
an anxiety diagnosis or use of anxiolytics at the same time as being
prescribed antidepressants, were excluded in study 3, also a
circumstance which would diminish the risk of depression development, as
this condition, especially in young women, is often associated with
anxiety disorders.

These three methodological circumstances are likely the main reason for
the discrepancies in results between study 1 and 2 versus study 3.

\emph{Reference population}

When women start using HC, some will within days, weeks, or months
experience mood deterioration or even depression due to that use, and
will, therefore, stop using these products. These former users are at an
increased risk of depression -- not due to their former use of HC, but
that use was the first test to reveal their mental sensitivity. In
addition, during the study period some users of HC will develop mood
deterioration without getting a prescription of anti-depressants or a
depression diagnosis, e.g., those seeking psychological therapy, and
will stop using HC. Both of these groups of previous users will be at an
increased risk of depression and use of antidepressants. By including
those women in the reference group of non-users, will underestimate the
risk of depression development in current users.

In pharmacoepidemiology it is default practice to compare exposed women
with non-exposed women. For rare outcomes it doesn't make any difference
whether non-exposed or never exposed are used as reference population.
But with a frequent outcome, such as depression development, it makes a
huge difference, which was illustrated in study 1, where the risk of
depression with use of oral contraceptives changed from 23\% increased
risk to 70\% increased risk with change in reference group from
non-users to never-users. In study 3 the risk of depression with HC use
changed from 1\% increased risk to 29\% increased risk with the same
change in reference group.

\emph{Covariates}

Generally, adjustments beyond age, calendar year and length of education
rarely make substantial changes in risk estimates in epidemiological
studies, including studies on risks and benefits of oral contraceptives.
Nevertheless, a missing potential confounder is often claimed as
invalidating a study if the message or results is disliked. An example
is the missing control for family disposition of depression in study 1
and 2. That variable was included in study 3 and turned out not to be a
confounder at all, indicating that when HC is prescribed, family history
of psychiatric diseases is rarely taken into consideration.

Interpretation

In medical science it is generally attempted to avoid ideological
influences, e.g. a researchers own feelings about the scientific issue,
and commercial interests. I am not doubting that all three research
teams of the three studies attempted this scientific goal. Nevertheless,
as we will see, also ideological issues apply to this scientific topic.

Ideological influences are often revealed in the introduction and
discussion section but may also be apparent in methodological choices. I
think it is fair to say that most gynaecologists are appreciating
hormonal contraception, because HC beyond being an effective
contraceptive method, also provide several important non-contraceptive
benefits for diseases treated in gynaecology, e.g. endometriosis and
polycystic ovary syndrome. Therefore, doctors in this specialty are
default sceptic about claimed adverse effects. Add to this the
historical resistance towards hormonal contraception from religious
bodies such as the catholic church, a fight still ongoing from
contraceptive and gynaecological societies.

Adverse effects of HC are much more recognised by clinicians dealing
with these effects, it being thrombosis or depression. Few cardiologists
doubt the increased thrombosis risk with oral contraceptives, because
they see these women in their clinical work. Gynaecologist never see
them and are often of the opinion that we are talking about very rare
events, which also vanish by length of use.

Likewise, few psychiatrists doubt that HC might induce depression. They
see them daily in their clinical work.

It is far from random, where studies claiming adverse events with HC use
are published. Of the three studies investigated here, the first was
published in a psychiatric journal, study 2 was published in a medical
journal, whereas publication 3 with the headline: ``There is no
association between combined oral hormonal contraceptives and
depression'' was published in a gynaecological journal. It is
questionable whether this headline is appropriately describing a study
demonstrating significantly increased risks of depression development in
five of six product groups examined applying never-users as reference
group.

I don't need to guess, which of the authors of the three studies will be
invited to company sponsored congresses in contraception or gynaecology
the coming years to present their results, further confirming doctors of
different specialties in their respective echo chambers.

Ideological influences are also apparent in the discussion section of
the three studies. Whereas the authors in study 1 and study 2 were
concerned about the \emph{healthy user effect} , which is
the\emph{attrition of susceptible} women by time of use, as those
experiencing side effects stop using the product, leaving those without
mental side effect in the still user cohort. That circumstance partly
explains the decreasing relative risk of depression with length of use.
But the sensitivity is also decreasing with increasing age, demonstrated
by the low relative risk of depression among those starting use of HC at
an advanced age\textsuperscript{1}.

The authors of study 3, on the other hand, were concerned about
overestimating the risk of HC due to medical conditions indicating this
treatment, e.g., endometriosis or polycystic ovary syndrome, both of
which dispose for depression development (even though they controlled
for these diseases).

About the increased risk of non-oral combined products (vaginal ring and
patches) the authors of paper 3 state; ``there is no clear biological
explanation for the higher risk estimates for non-oral products''. That
is not quite true, as the plasma levels of ethinylestradiol in users of
patches have been shown to be substantially higher than the levels of
the external hormones in users of oral contraceptives with the same
hormone types\textsuperscript{4}. The demonstrated difference in risk
was therefore to be expected.

And the increased risk of depression with hormone intrauterine devices
is in paper 3 explained by the attempt to provide women with mental
challenges an effective and user-independent method, which was not
controlled for\textsuperscript{3}. Thus, the main concern in the
discussion of paper 3 focuses on the likely overestimation of the risk
of depression with use of hormonal contraception and suggests the
differences to other studies to be a result of residual confounding.

It is difficult not to explain the very different focus in the
discussion of the three papers by different views on HC in general among
the (senior) authors of the three publications.

Finally, the authors of study 3 find support from randomised studies.
The two referred studies found no deterioration in depressive symptoms.
But randomised studies are not free of bias.

If women are invited to participate in a randomised study on hormonal
contraceptive adverse effects, those having previous bad experience with
HC will typically decline participation, while those having good
experiences with previous use of HC, will be prone for accepting
participation. Unless a randomised study demands no previous use of HC
among the participants, these studies will a priori be biased towards
underestimating adverse effects. None of the two mentioned randomised
studies made such a demand, and that likely bias was not recognised of
the authors of paper 3.

\textbf{Conclusion}

This in detail review of three Scandinavian large-scale studies dealing
with the influence of hormonal contraception on the risk of depression
development reveals methodological choices as a likely explanation for
the different findings in the three studies. Further that residual
confounding is an unlikely reason for the divergent results, and that
ideological circumstances might have a main responsibility for the
methodological choices, and the different interpretation of the results
in the three studies.

\textbf{Acknowledgements}

\emph{Conflicts of interests}

The author was co-author of study 1, and reviewer of study 3. As
reviewer I never saw nor recommended the final version of the paper
published.

My institution The Julie Marie Center, Rigshospitalet, has received
grants for covering expenses of pharmacoepidemiologic studies on
hormonal contraceptive use and adverse effects. The author did not
receive any honoraria from these grants.



\textbf{References}

\begin{enumerate}
\tightlist
\item
  Skovlund CW, Morch LS, Kessing LV, Lidegaard Ø. Association of
  hormonal contraception with depression. JAMA Psychiatry 2016; 73:
  1154--62.
\item
  Zettermark S, Perez VR, Merlo J. Hormonal contraception increases the
  risk of psychotropic drug use in adolescent girls but not in adults: a
  pharmacoepidemiological study on 800 000 Swedish women. PLoS One 2018;
  13: e0194773.
\item
  Lundin C. Wikman A, Lampa E, Bixo M, Gemzell-Danielsson K, Wikman P,
  Ljung R, Poromaa IS. There is no association between combined oral
  hormonal contraceptives and depression: a Swedish register-based
  cohort study. BJOG 2021; https://doi.org/10.1111/1471-0528.17028.
\item
  Van den Heuvel MW, van Bragt AJM, Alnabawy A, Kaptein MC. Comparison
  of ethinylestradiol pharmacokinetics in the transdermal patch, and an
  oral contraceptive. \emph{Contraception} 2005; 72: 168-74.
\end{enumerate}

\emph{}

\textbf{Table 1}

\emph{Key features of three recently conducted Scandinavian studies
assessing the risk of depression with use of hormonal contraception,}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
First author\textsuperscript{ref} & Skovlund\textsuperscript{1} &
Skovlund\textsuperscript{1} & Zettermark\textsuperscript{2} &
Zettermark\textsuperscript{2} & Lundin\textsuperscript{3} &
Lundin\textsuperscript{3}\tabularnewline
\midrule
\endhead
& Design and population & Design and population & Design and population
& Design and population & Design and population & Design and
population\tabularnewline
Study design & Historical cohort & Historical cohort & Historical cohort
& Historical cohort & Historical cohort & Historical
cohort\tabularnewline
Study period & 2000-2013 & 2000-2013 & 2010-2011 & 2010-2011 & 2010-2017
& 2010-2017\tabularnewline
Population & 1.061.997 & 1.061.997 & 815.662 & 815.662 & 739.585 &
739.585\tabularnewline
Age group & 15-34 years & 15-34 years & 12-30 years & 12-30 years &
15-25 years & 15-25 years\tabularnewline
Person-years & 6,832,938 & 6,832,938 & 815,662 & 815,662 & 3,044,372 &
3,044,372\tabularnewline
Non-use & 3,041,595 & 3,041,595 & 404,103 & 404,103 & 1,947,129 &
1,947,129\tabularnewline
All use & 3,791,343 & 3,791,343 & 411,559 & 411,559 & 1,097,243 &
1,097,243\tabularnewline
& Results & Results & Results & Results & Results &
Results\tabularnewline
Reference group & Non-users & Non-users & Non-users & Non-users &
Non-users & Non-users\tabularnewline
\emph{Age group (all)} & \emph{15-34 years} & \emph{15-34 years} &
\emph{12-30 years} & \emph{12-30 years} & \emph{15-25 years} &
\emph{15-25 years}\tabularnewline
& \textbf{RR~} & \textbf{5\% CI} & \textbf{OR~} & \textbf{95\% CI} &
\textbf{RR~} & \textbf{95\% CI}\tabularnewline
Oral contraceptives & 1.2 & 1.22-1.25 & 1.3 & 1.26-1.33 & 0.9 &
0.87-0.91\tabularnewline
Transdermal patch & 2.1 & 1.76-2.18 & \textgreater{} 1.6 & 1.45-1.67 &
1.3 & 1.21-1.33\tabularnewline
Vaginal ring & 1.5 & 1.55-1.69 & & & &\tabularnewline
Progestogen only pill & 1.3 & 1.18-1.37 & 1.3 & 1.24-1.33 & 1.0 &
0.99-1.06\tabularnewline
LNG-IUS & 1.4 & 1.31-1.42 & 1.5 & 1.38-1.55 & 1.3 &
1.29-1.39\tabularnewline
\emph{Adolescents} & \emph{15-19 years} & \emph{15-19 years} &
\emph{15-17 years} & \emph{15-17 years} & \emph{15-19 years} &
\emph{15-19 years}\tabularnewline
Oral contraceptives & 1.8 & 1.75-1.84 & 1.5 & 1.41-1.64 & 1.0 &
0.93-0.98\tabularnewline
Transdermal patch & 3.1 & 2.56-3.71 & \textgreater{} 2.3 & 1.85-2.79 &
1.4 & 1.30-1.58\tabularnewline
Vaginal ring & 2.9 & 2.60-3.16 & & & &\tabularnewline
Progestogen only pill & 2.1 & 1.67-2.52 & 1.8 & 1.65-2.03 & 1.1 &
1.07-1.19\tabularnewline
LNG-IUS & 3.1 & 2.47-3.84 & 2.5 & 2.10-2.94 & 1.6 &
1.46-1.73\tabularnewline
Reference group & Never users & Never users & & & Never users & Never
users\tabularnewline
\emph{Age group} & \emph{15-34 years} & \emph{15-34 years} & & &
\emph{15-25 years} & \emph{15-25 years}\tabularnewline
Oral contraceptives & 1.7 & 1.66-1.71 & NA & NA & 1.0 &
0.98-1.02\tabularnewline
Transdermal patch & 2.6 & 2,38-2,95 & NA & NA & \textgreater{} 1.3 &
1.27-1.39\tabularnewline
Vaginal ring & 2.2 & 2.14-2.34 & NA & NA & &\tabularnewline
Progestogen only pill & 1.7 & 1.62-1.87 & NA & NA & 1.1 &
1.07-1.14\tabularnewline
LNG-IUS & 1.9 & 1.80-1.96 & NA & NA & 1.4 & 1.32-1.42\tabularnewline
\bottomrule
\end{longtable}

\emph{RR = relative risk (or rate ratio), OR = Odds ratio, LNG-IUS=
levonorgestrel releasing intrauterine system}

\textbf{Table 2}

\emph{Methodological choices likely influenced by ideologies towards
hormonal contraception}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{First author\textsuperscript{ref}} &
\textbf{Skovlund\textsuperscript{1}} &
\textbf{Zettermark\textsuperscript{2}} &
\textbf{Lundin\textsuperscript{3}}\tabularnewline
\midrule
\endhead
Methodological choices & Methodological choices & Methodological choices
& Methodological choices\tabularnewline
Inclusion of the youngest women & Yes & Yes & No\tabularnewline
Following women from start of HC use & Yes & Yes & No\tabularnewline
Including events first months after HC start & Yes & Yes &
No\tabularnewline
Including women having used HC before 15 years & Yes & Yes &
No\tabularnewline
Using ''never-users'' as main reference group & No & No &
No\tabularnewline
Presenting results also with never-users as reference & Yes & No &
Yes\tabularnewline
Considering never-users as the least biased ref. group & Yes & Na &
No\tabularnewline
Including depression with other simultaneous mental diseases* & Yes &
Yes & No\tabularnewline
Making up depression separately & Yes & No & Yes\tabularnewline
Ideological choices & & &\tabularnewline
Balanced headline\selectlanguage{ngerman}\textsuperscript{¤} & Yes & Yes & No\tabularnewline
Conservative interpretation of misclassification & Yes & Yes &
No\tabularnewline
Randomised studies may be invalidated'' & Yes & No & No\tabularnewline
\bottomrule
\end{longtable}

\emph{*) Was depression occurring at the same time as other behavioral
disorders such as anxiety disorders included as outcomes among exposed
in the study?}

\selectlanguage{ngerman}\emph{\textsuperscript{¤}) Balanced headline indicates whether the
headline of the study is reflecting the underlying study results.}

\emph{``) Did the authors acknowledge the limitation of randomized
studies not demanding never-use of hormonal contraceptives among its
participants}

\selectlanguage{english}
\FloatBarrier
\end{document}

