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Treatment of Peripartum Depression with Antidepressants and Other Psychotropic Medications: A Synthesis of Clinical Practice Guidelines in Europe

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This study examined (1) the availability and content of national CPGs for treatment of peripartum depression, including comorbid anxiety, with antidepressants and other psychotropics across Europe and (2) antidepressant and other psychotropic utilization data as an indicator of prescribers’ compliance to the guidelines. We conducted a search using Medline and the Guidelines International Network database, combined with direct e-mail contact with national Riseup-PPD COST ACTION members and researchers within psychiatry. Of the 48 European countries examined, we screened 41 records and included 14 of them for full-text evaluation. After exclusion of ineligible and duplicate records, we included 12 CPGs. Multiple CPGs recommend antidepressant initiation or continuation based on maternal disease severity, non-response to first-line non-pharmacological interventions, and after risk-benefit assessment. Advice on treatment of comorbid anxiety is largely missing or unspecific. Antidepressant dispensing data suggest general prescribers’ compliance with the preferred substances of the CPG, although country-specific differences were noted. To conclude, there is an urgent need for harmonized, up-to-date CPGs for pharmacological management of peripartum depression and comorbid anxiety in Europe. The recommendations need to be informed by the latest available evidence so that healthcare providers and women can make informed, evidence-based decisions about treatment choices.
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Citation: Kittel-Schneider, S.; Felice,
E.; Buhagiar, R.; Lambregtse-van den
Berg, M.; Wilson, C.A.; Banjac Baljak,
V.; Vujovic, K.S.; Medic, B.;
Opankovic, A.; Fonseca, A.; et al.
Treatment of Peripartum Depression
with Antidepressants and Other
Psychotropic Medications: A
Synthesis of Clinical Practice
Guidelines in Europe. Int. J. Environ.
Res. Public Health 2022,19, 1973.
https://doi.org/10.3390/
ijerph19041973
Academic Editor: Francesca
Agostini
Received: 27 November 2021
Accepted: 29 January 2022
Published: 10 February 2022
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4.0/).
International Journal of
Environmental Research
and Public Health
Review
Treatment of Peripartum Depression with Antidepressants and
Other Psychotropic Medications: A Synthesis of Clinical
Practice Guidelines in Europe
Sarah Kittel-Schneider 1, Ethel Felice 2, Rachel Buhagiar 3, Mijke Lambregtse-van den Berg 4,
Claire A. Wilson 5,6 , Visnja Banjac Baljak 7, Katarina Savic Vujovic 8, Branislava Medic 8, Ana Opankovic 9,
Ana Fonseca 10 and Angela Lupattelli 11, *
1Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Würzburg,
D-97080 Würzburg, Germany; Kittel_S@ukw.de
2Department of Psychiatry, Faculty of Medicine & Surgery Msida, University of Malta, 2080 Majjistral, Malta;
ethelfelice@gmail.com
3Health-Mental Health Services, 2080 Majjistral, Malta; rachel.buhagiar@gov.mt
4Departments of Psychiatry and Child & Adolescent Psychiatry, Erasmus University Medical Center,
3015 GD Rotterdam, The Netherlands; mijke.vandenberg@erasmusmc.nl
5Section of Women’s Mental Health, King’s College London, London SE5 8AF, UK; claire.1.wilson@kcl.ac.uk
6South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital Monks Orchard Road,
Beckenham BR3 3BX, UK
7Clinic of Psychiatry, University Clinical Center of the Republic of Srpska,
78000 Banjaluka, Bosnia and Herzegovina; visnjab76@hotmail.com
8Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine,
University of Belgrade, P.O. Box 38, 11129 Belgrade, Serbia; katarinasavicvujovic@gmail.com (K.S.V.);
brankicamedic@gmail.com (B.M.)
9Clinic for Psychiatry, University Clinical Center, 11000 Belgrade, Serbia; ana.opankovic@gmail.com
10 Center for Research in Neuropsychology and Cognitive-Behavioral Intervention, University of Coimbra,
3000-115 Coimbra, Portugal; ana.fonseca77@gmail.com
11 PharmacoEpidemiology and Drug Safety Research Group, Department of Pharmacy, PharmaTox Strategic
Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway
*Correspondence: angela.lupattelli@farmasi.uio.no
Abstract:
This study examined (1) the availability and content of national CPGs for treatment of
peripartum depression, including comorbid anxiety, with antidepressants and other psychotropics
across Europe and (2) antidepressant and other psychotropic utilization data as an indicator of
prescribers’ compliance to the guidelines. We conducted a search using Medline and the Guidelines
International Network database, combined with direct e-mail contact with national Riseup-PPD
COST ACTION members and researchers within psychiatry. Of the 48 European countries examined,
we screened 41 records and included 14 of them for full-text evaluation. After exclusion of ineligible
and duplicate records, we included 12 CPGs. Multiple CPGs recommend antidepressant initiation
or continuation based on maternal disease severity, non-response to first-line non-pharmacological
interventions, and after risk-benefit assessment. Advice on treatment of comorbid anxiety is largely
missing or unspecific. Antidepressant dispensing data suggest general prescribers’ compliance with
the preferred substances of the CPG, although country-specific differences were noted. To conclude,
there is an urgent need for harmonized, up-to-date CPGs for pharmacological management of
peripartum depression and comorbid anxiety in Europe. The recommendations need to be informed
by the latest available evidence so that healthcare providers and women can make informed, evidence-
based decisions about treatment choices.
Keywords:
clinical practice guideline; depression; anxiety; antidepressant; psychotropic
medications; peripartum
Int. J. Environ. Res. Public Health 2022,19, 1973. https://doi.org/10.3390/ijerph19041973 https://www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2022,19, 1973 2 of 17
1. Introduction
Peripartum or perinatal depression, which is depression arising in the period between
the start of a pregnancy and the end of the first postpartum year, to use a broad definition,
affects approximately one in eight women [
1
]. Peripartum and perinatal depression are
used interchangeably, although the former term relates more specifically to the woman.
The disorder often persists throughout the peripartum period, with as many as 47% of
women with postnatal depression having experienced an antenatal episode [
2
]. In many
cases, depression concurs with anxiety, and this adds a substantial mental health burden to
the woman [
3
]. One recent study has proposed multiple subtypes of perinatal depression,
which differ in terms of symptom dimension and time of onset [
4
]. Women may, there-
fore, need tailored treatment strategies, including pharmacotherapy, depending on their
individual depression course, timing of onset, and prominent symptom typology.
Perinatal depression is associated with a spectrum of obstetric and long-term negative
outcomes in the offspring [
5
,
6
], including possible adverse impacts on the mother-infant
relationship [
7
,
8
]. It also substantially affects women’s well-being and functioning, and it
can even lead to suicide [
9
]. In moderate to severe cases or after non-response to first-line
psychotherapy, pharmacotherapy with antidepressants is often needed [
10
]. Pooled results
from 40 cohort studies [
11
] indicate that selective serotonin reuptake inhibitors (SSRIs) are
the most commonly used antidepressants, with a population prevalence of filled prescrip-
tions ranging from 3.5% before pregnancy to 3.0% during gestation and 4.7% in the first
year postpartum. Augmentation with antipsychotics or adjuvant pharmacotherapy with
benzodiazepines or sedative antihistamines may be needed in some cases [
10
]. Neverthe-
less, pregnancy remains a major driver for discontinuation of antidepressants, and 49% of
those individuals who chose to continue have low antidepressant adherence [12,13].
The decision-making process about antidepressant treatment during pregnancy or
lactation is complex, as it involves weighing the possible risk of exposure in utero or
in breast milk against the potential adverse effects of sub-optimally treated maternal
peripartum depression to both the mother and child. Clinical practice guidelines (CPGs) for
peripartum depression management may facilitate this decision-making process. However,
many countries have not established CPGs for peripartum depression, and for those
available, the recommendations are not always uniform [
14
]. In 2018, one systematic review
evaluated the content of the available CPGs, and it was found that only four countries
recommend continuation into pregnancy of a pre-existing antidepressant treatment [
14
].
This prior work extracted only recommendations from CPGs adhering to the quality criteria
of the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument. Thus,
there are still knowledge gaps on current clinical practices from CPGs not meeting such
quality criteria. Furthermore, the extent to which national CPGs are followed in relation to
antidepressant and other psychotropic prescribing remains unknown.
Therefore, the aim of this review was to examine the availability of national CPGs
for treatment of peripartum depression with antidepressants across Europe and review
their content and recommendations for the pregnancy and postpartum periods. We fur-
ther evaluate antidepressant utilization data in women during the perinatal period as an
indicator of compliance to the guidelines. To shed additional light on mental disorder
co-morbidity, we evaluated whether CPGs for peripartum depression provide guidance
on psychopharmacological treatment for co-morbid anxiety, along with prescription fill
data for other psychotropics (i.e., antipsychotics and benzodiazepines) and sedative anti-
histamines during pregnancy and postpartum.
2. Materials and Methods
2.1. Search and Selection Criteria for Clinical Practice Guidelines
We conducted an extensive search of CPGs for treatment of peripartum depression
in 48 countries in Europe, including member countries of the European Union, Schengen
states, and other European countries. San Marino and the Holy See, both located geograph-
ically in Italy, were not included, as the former follows guidelines in Italy and the latter was
Int. J. Environ. Res. Public Health 2022,19, 1973 3 of 17
not relevant. We combined multiple search strategies. First, we searched the literature in the
Medline database (via PubMed) from inception to 31 August 2021 using the free text terms
“antidepressant, peripartum, perinatal, pregnancy, postpartum, antenatal period, prenatal
period, postnatal period, depression, mental health, psychiatric” and applied the filter for
guidelines only. Second, we searched the Guidelines International Network (GIN) database
using the terms “depression, peripartum, perinatal, pregnancy” on
31 August 2021
. Third,
we contacted directly via email the national members of Riseup-PPD COST ACTION
(CA18138–Research Innovation and Sustainable Pan-European Network in Peripartum De-
pression Disorder) with an inquiry about the existence of a CPG for peripartum depression
in the country. Last, we contacted researchers within peripartum psychiatry in various
countries. No exclusion criteria were employed based on language. In the searches in
Medline and GIN, we did not include published CPGs from countries outside Europe. We
did not restrict the search to CPGs meeting the quality criteria of the AGREE instrument,
as we aimed to gather as much information as possible about current clinical practices.
Case reports and animal studies were excluded. We excluded CPGs on depression or
mental health in adults which did not cover or mention peripartum depression within
them and CPGs on peripartum depression that did not mention pharmacotherapy inter-
ventions. Clinical recommendations without clear references or without a description of
the process that led to the recommendation were also excluded. The literature searches and
abstract screenings were performed by a single author. The selection of the CPGs eligible
for inclusion were agreed upon by all authors.
Data abstraction was performed by one author depending on the relevant language
and, thereafter, quality-checked by another author. We extracted recommendations re-
garding (1) initiation, continuation or discontinuation, and switching of the antidepressant
for both new and preexisting depression in pregnancy or postpartum, (2) preferred and
non-preferred antidepressants in pregnancy and while breastfeeding, (3) compatibility of
antidepressants with breastfeeding, (4) antidepressant level monitoring or dose adjustment,
and (5) recommendations for pharmacological treatment of comorbid anxiety in pregnancy
and postpartum.
2.2. Search and Selection Criteria for Antidepressant and Psychotropic Utilization Studies
We searched the literature in the Medline database (via PubMed) from inception to
31 August 2021 using the free text terms “antidepressant, psychotropic, antipsychotic,
anxiolytic, “medication use”, “drug use”, peripartum, perinatal, pregnancy, postpartum,
antenatal period, prenatal period, postnatal period, depression, mental health, psychiatric”.
We extracted the most complete or recent antidepressant drug utilization studies among
those published in the last 10–15 years originating from countries in Europe. We applied no
restriction as to the way antidepressant use in pregnancy and postpartum was measured
in the studies (e.g., based on self-reporting, prescription fills, or medical records). The
outcome criteria were prevalence estimates for antidepressant use before, during, and
after pregnancy. The same criteria applied to the search and data extraction for other
psychotropic medications. If available, we extracted prevalence estimates from more than
one study.
2.3. Ethics Statement
No ethics approval was sought, as this review evaluated existing clinical practice
guidelines. No informed consent was collected, as the study did not involve patients. The
synthesis was not registered in PROSPERO.
3. Results
3.1. Identified Clinical Practice Guidelines
Figure 1describes the flow diagram of the various search strategies to achieve the final
sample of CPGs included in the study. Across the 48 countries examined, we were unable
to identify a contact person or did not receive a response in 22 (45.8%) of the countries.
Int. J. Environ. Res. Public Health 2022,19, 1973 4 of 17
We received a response or identified a CPG in the literature search for
26 countries
in
Europe, of which 10 (38.5%) (i.e., Austria, Bulgaria, Croatia, Cyprus, France, Greece,
Iceland, Portugal, Turkey, and Bosnia and Herzegovina) did not have a national CPG for
intervention strategies of peripartum depression or mental health, either specific or broader
for the adult population, with mention of the peripartum population. In Ireland, we could
only retrieve an information leaflet on peripartum depression for women, which is not
classified as a CPG. In Ukraine (personal communication), the criteria for treatment of
peripartum depression were reported to be in place, which included pharmacotherapy
interventions with amitriptyline, phenazepam, relanium, frenolone, and with vitamins
(e.g., ascorbic acid). However, no further information was obtained. Belgium and Sweden
used protocols or guidelines for screening and treatment of peripartum depression based
on international guidelines (NICE). However, pharmacotherapy interventions are not
mentioned [
15
,
16
]. Of the searches in PubMed and the GIN database, we screened three
CPGs from Spain, Poland, and the UK, which were duplicates of the ones obtained via the
contact persons in these countries. We included and fully evaluated 12 CPGs. In the CPG
from Latvia, recommendations on pharmacological interventions were only provided for
the postpartum period.
Int. J. Environ. Res. Public Health 2022, 19, x 4 of 17
2.3. Ethics Statement
No ethics approval was sought, as this review evaluated existing clinical practice
guidelines. No informed consent was collected, as the study did not involve patients. The
synthesis was not registered in PROSPERO.
3. Results
3.1. Identified Clinical Practice Guidelines
Figure 1 describes the flow diagram of the various search strategies to achieve the
final sample of CPGs included in the study. Across the 48 countries examined, we were
unable to identify a contact person or did not receive a response in 22 (45.8%) of the coun-
tries. We received a response or identified a CPG in the literature search for 26 countries
in Europe, of which 10 (38.5%) (i.e., Austria, Bulgaria, Croatia, Cyprus, France, Greece,
Iceland, Portugal, Turkey, and Bosnia and Herzegovina) did not have a national CPG for
intervention strategies of peripartum depression or mental health, either specific or
broader for the adult population, with mention of the peripartum population. In Ireland,
we could only retrieve an information leaflet on peripartum depression for women, which
is not classified as a CPG. In Ukraine (personal communication), the criteria for treatment
of peripartum depression were reported to be in place, which included pharmacotherapy
interventions with amitriptyline, phenazepam, relanium, frenolone, and with vitamins
(e.g., ascorbic acid). However, no further information was obtained. Belgium and Sweden
used protocols or guidelines for screening and treatment of peripartum depression based
on international guidelines (NICE). However, pharmacotherapy interventions are not
mentioned [15,16]. Of the searches in PubMed and the GIN database, we screened three
CPGs from Spain, Poland, and the UK, which were duplicates of the ones obtained via the
contact persons in these countries. We included and fully evaluated 12 CPGs. In the CPG
from Latvia, recommendations on pharmacological interventions were only provided for
the postpartum period.
Figure 1. Flow chart of the review process for the clinical practice guideline synthesis. Abbrevia-
tions: CPG = clinical practice guideline; GIN = Guidelines International Network. * No response or
identification in Albania, Andorra, Armenia, Azerbaijan, Belarus, Croatia, Czech Republic, Esto-
nia, Georgia, Hungary, Kazakhstan, Kosovo, Liechtenstein, Luxembourg, Moldova, Montenegro,
North Macedonia, Romania, Russia, Slovakia, Slovenia, and Switzerland.
Figure 1.
Flow chart of the review process for the clinical practice guideline synthesis. Abbreviations:
CPG = clinical practice guideline; GIN = Guidelines International Network. * No response or
identification in Albania, Andorra, Armenia, Azerbaijan, Belarus, Croatia, Czech Republic, Estonia,
Georgia, Hungary, Kazakhstan, Kosovo, Liechtenstein, Luxembourg, Moldova, Montenegro, North
Macedonia, Romania, Russia, Slovakia, Slovenia, and Switzerland.
3.2. Pharmacological Interventions for Treatment of Antenatal Depression
Table 1shows that most CPGs advise initiation of antidepressants in women with new
onset or moderate-to-severe antenatal depression. This treatment should be undertaken af-
ter an individualized risk–benefit evaluation and following non-response to psychotherapy.
In contrast, the CPG in Poland discourages the use of antidepressants in the first trimester
and states that this medication should be discontinued before delivery. All the CPGs seem
unanimous in recommending or mentioning the possibility to continue antidepressants
in pregnancy for preexisting moderate-to-severe depression (Table 1). In the UK CPG,
monotherapy (if possible) and the lowest effective dose are advised in the context of both
initiation and continuation of the antidepressant. On the basis of filled prescription and
drug utilization data, there was a decrease in the prevalence of antidepressant use from
Int. J. Environ. Res. Public Health 2022,19, 1973 5 of 17
preconception (range: 1.6–9.6%) into pregnancy (range: 0.3–4.1%), with SSRI being the most
commonly prescribed group in most countries (Table 1). For many countries in Eastern
Europe, no such utilization data were available.
There is general agreement between the CPGs in evaluating individual drug response
in the period prior to pregnancy in the decision making about antidepressant continu-
ation during pregnancy. The CPGs provide less uniform guidance regarding switching
antidepressants during pregnancy (Table 1). In the CPGs of Malta and Norway, switch-
ing is discouraged unless the drug is ineffective. The CPG in the Netherlands considers
switching from paroxetine to a preferred antidepressant but before pregnancy. Multiple
CPGs (Finland, Germany, Italy, and Serbia) do not provide guidance on switching. Like-
wise, information on antidepressant level monitoring in serum or plasma and on dosage
adjustment is missing for the CPGs in Italy and Denmark.
Multiple CPGs mention sertraline and citalopram as preferred antidepressants in preg-
nancy, whereas others (i.e., Finland, Serbia, and Spain) list the class of SSRIs. Paroxetine
was mentioned as not a preferred antidepressant in most CPGs, except for Serbia, the
UK, and Norway. In the two latter countries, the CPGs advise basing the choice of the
antidepressant on maternal prior response and its safety profile. Generally, the antidepres-
sants recommended in the CPGs were also the ones most often used in gestation, except
in Denmark (for fluoxetine), the Netherlands and Spain (for paroxetine), and Germany
(for amitriptyline). Paroxetine ranked among the most commonly used antidepressants in
pregnancy in specific countries (i.e., Italy, the Netherlands, or Spain).
3.3. Pharmacological Interventions for Treatment of Postpartum Depression
Table 2summarizes the content and recommendations of the CPGs for the postpar-
tum period. Most CPGs (n= 11) recommend initiation or continuation of antidepressant
medications in women suffering from depression in the postpartum period. Nearly all
CPGs suggest an individual risk–benefit evaluation of the antidepressant treatment in the
case of breastfeeding. Recommendations about breastfeeding compatibility with maternal
antidepressant use were not specified in three GPGs (Spain, Serbia, and Norway). The
CPGs in the Netherlands, Italy, and Finland state that antidepressant use does not pre-
vent breastfeeding, whereas the UK and Denmark advise closely monitoring the exposed
breastfed infant for potential adverse effects, such as weight gain. The Maltese CPG ad-
vises that only healthy and full-term infants should be breastfed when mothers are taking
antidepressants. The Polish CPG gives a detailed recommendation about the timing of
antidepressant intake and breastfeeding (i.e., to take one daily dose before the longest sleep
of the child and breastfeed directly before that). Recommendations about switching antide-
pressants are either unspecified (n= 5) in the CPG or discouraged, especially if it affects
the woman. The prevalence estimates of antidepressant use postpartum were greater than
in the antenatal period and generally returned to the magnitude seen pre-pregnancy. For
most of the countries included in this work, no antidepressant utilization data postpartum
are available.
Int. J. Environ. Res. Public Health 2022,19, 1973 6 of 17
Table 1.
Overview of recommendations in the CPGs about antidepressant treatment in women with antenatal depression, with prevalence estimates of antidepressant
and other psychotropic medication use in the country.
Country,
Publication Year,
Type
New Depression,
Initiate AD
Preexisting
Depression,
Continue AD
AD Dose
Adjustment and
Monitoring
Switching AD Preferred or
Not Preferred AD
AD Use before vs
during Pregnancy
(%)
Most Common
ADs Used during
Pregnancy
Treatment of
Co-Morbid
Anxiety
Other Psychotropics
during Pregnancy (%)
Denmark [17]
PMH-S
Yes, if severe and no
response to
psychotherapy Yes NS Yes, if effective for
woman’s depression
Sertraline,
citalopram
/
Paroxetine,
fluoxetine
2.0 vs.
1.9–4.1 [18,19]
Citalopram,
sertraline,
fluoxetine [19]NS BZD: 0.6 [20]
AP: 0.4 [21]
Quetiapine: 0.2 [21]
Finland [22] N-PPD NS
Yes, in
moderate-to-severe
cases
Psychotherapy first
line
Monitoring of
response is
important NS
SSRIs
/
Paroxetine,
fluoxetine,
tricyclics
1.6–4.0 [23] vs.
3.6* [24]NA NS
BZD: 1.2* [25]
AP: 0.8 [21]
Quetiapine: 0.9
[21]
Germany [26]
N-PPD
Yes, after individual
risk benefit
evaluation,
individual disease
history, preference
and availability of
alternative
treatments
Yes, in
moderate-to-severe
cases. Abrupt
discontinuation is
discouraged.
Psychotherapy first
line
Monotherapy if
possible, lowest
effective dose
Continuous
measurement of
plasma levels
NS
Sertraline,
citalopram
/
Paroxetine,
fluoxetine
4.0 [27] vs.
0.4 (unpublished
data)
Amitriptyline,
(es)citalopram,
sertraline
(unpublished data)
NS
BZD: 3.3 [25]
AP: 0.3 [21]
Quetiapine: 0.2
[21]
Italy [28]
PMH-S
Yes, after individual
risk–benefit
assessment
Yes, after individual
risk–benefit
assessment NS NS NS 3.3–4.4 [29] vs.
1.2–1.6 [29]
Paroxetine,
sertraline,
citalopram [29]
Yes, BZD can be
used
BZD: 1.4 [30]
AP: 0.8 [31]
Quetiapine: NA
SAH: 0.4* [24]
Malta [32]
PMH-S
Yes, after individual
risk–benefit
assessment; drug
choice based on
lowest risk,
monotherapy if
possible and at the
lowest effective dose
Yes, after individual
risk-benefit
assessment; drug
choice based on
lowest risk,
monotherapy if
possible and at the
lowest effective dose;
previous response is
considered
NS If possible, switch
paroxetine to other
SSRI
Sertraline ¥;
Fluoxetine
/
Paroxetine
NA Sertraline,
fluoxetine
(unpublished data)
BZD only short
term for extreme
anxiety or agitation;
BZD should be
avoided in late
pregnancy
BZD: NA
AP: NA
Quetiapine: NA
The Netherlands [33]
PMH-S
Yes, after individual
risk–benefit
assessment
Yes, if woman is
stable with
medication
Yes, lowest effective
dose; paroxetine
preferably not >20
mg/day
If possible, switch
paroxetine to other
SSRI but
pre-pregnancy
Sertraline ¥
/
Paroxetine ¥
3.9 vs.
2.1 [34]
Sertraline,
paroxetine,
citalopram [34]NS BZD: 1.1 [25,35]
AP: NA
Quetiapine: NA
Int. J. Environ. Res. Public Health 2022,19, 1973 7 of 17
Table 1. Cont.
Country,
Publication Year,
Type
New Depression,
Initiate AD
Preexisting
Depression,
Continue AD
AD Dose
Adjustment and
Monitoring
Switching AD Preferred or
Not Preferred AD
AD Use before vs
during Pregnancy
(%)
Most Common
ADs Used during
Pregnancy
Treatment of
Co-Morbid
Anxiety
Other Psychotropics
during Pregnancy (%)
Norway [36] PMH-S
Yes,
if severe and with
non-
pharmacological
therapy
Yes,
after individual
risk–benefit
assessment.
Psychotherapy first
line.
Abrupt
discontinuation is
discouraged.
Yes, serum
concentration No
Choice based on
prior drug response
and its safety
profile
2.0 vs. 1.5
[37]
(Es)citalopram,
sertraline,
venlafaxine [19]NS
BZD: 0.9 [38]
AP: 1.2 [21]
Quetiapine: 0.3 [21]
SAH: 1.0 [24] *
Poland [39]
PMH-S
Individual
risk–benefit
assessment to be
made.
**AD in 1 trimester
should be avoided,
and AD should be
discontinued before
delivery
If severe depression
or ongoing
mild-to-moderate
symptoms, AD
should be
considered.
Gradual
discontinuation if
mild symptoms with
psychotherapy.
** As for new
depression.
Monotherapy,
lowest effective dose
Yes, switching an
AD which is
effective and offers
fewer adverse effects
NS
/
Paroxetine - vs. 0.3 [24] * NA
Yes, but do not
offer BZD except
for the short-term
treatment of severe
anxiety and
agitation
BZD: 0.2–14.0 [24,25] *
AP: NA
Quetiapine: NA
SAH: 0.4 [24] *
Serbia [40]
N-PPD
Yes,
if severe after
individual
risk–benefit
assessment
Yes, after individual
risk–benefit
assessment
Yes, serum
concentration NS
Fluoxetine,
citalopram,
fluvoxamine,
paroxetine,
sertraline
/
TCA
- vs. 0.3 [24] *
(Es)citalopram,
sertraline,
mirtazapine,
duloxetine
(unpublished data)
Yes,
BZD
BZD: 0.2–14.0 [24,25] *
AP: NA
Quetiapine: NA
SAH: 0.4 [24] *
Spain [41]
PMH-S
Yes, after individual
risk–benefit
assessment
Yes,
after individual
risk–benefit
assessment and
based on individual
drug response
Monotherapy if
possible, lowest
effective dose;
continuous
measurement of
plasma levels due to
fluctuations in
pregnancy is
recommended
Yes, if lower risk to
child and effective in
mothers
SSRIs
/
Paroxetine,
tricyclics,
fluoxetine
- vs. 0.5–0.8
[42,43]
Paroxetine,
citalopram,
fluoxetine44
Yes, but for acute
symptoms for
maximum 4 weeks
BZD: 1.9 [42]
AP: 0.1 [43]
Quetiapine: NA
Int. J. Environ. Res. Public Health 2022,19, 1973 8 of 17
Table 1. Cont.
Country,
Publication Year,
Type
New Depression,
Initiate AD
Preexisting
Depression,
Continue AD
AD Dose
Adjustment and
Monitoring
Switching AD Preferred or
Not Preferred AD
AD Use before vs
during Pregnancy
(%)
Most Common
ADs Used during
Pregnancy
Treatment of
Co-Morbid
Anxiety
Other Psychotropics
during Pregnancy (%)
United Kingdom
[44,45]
PMH-S
Yes, particularly for
moderate-to-severe
depression, after
discussing
with the woman the
risk–benefit
assessment of AD;
drug choice based
on lowest risk,
monotherapy if
possible and at the
lowest effective dose
Yes, particularly for
moderate-to-severe
depression, after
discussing with the
woman the
risk–benefit
assessment of AD;
monotherapy if
possible and at the
lowest effective dose
Yes, dosages may
need to be adjusted
in pregnancy
Option to be
discussed with the
woman but aim is to
expose fetus to as
few drugs as
possible
Unspecified, choice
based on prior drug
response and its
safety profile
8.8–9.6 vs.
3.7 [29]Fluoxetine,
citalopram [29]
Yes, with ADs. Do
not offer BZD
except for the
short-term
treatment of severe
anxiety and
agitation.
BZD: 1.2 * [25]
AP: 0.3–4.6 [21,46]
Quetiapine: 0.4 [21]
AD = antidepressant; BZD = benzodiazepines; AP = antipsychotics; SAH = sedative antihistamines; PMH-S = peripartum mental health-specific; N-PPD = not specific to peripartum
depression, but pregnant women are dealt with within the guideline for adult depression. Estimates of sedative antihistamines are only shown when available. As such, data are
lacking for most countries. * Average estimate for the region at aggregated level (non-country specific) or for the specific country within the meta-analysis.
¥
Applies to first episode in
pregnancy, when the woman starts on a new medication.
Table 2.
Overview of recommendations in the CPGs about antidepressant treatment in women with postnatal depression, with prevalence estimates of antidepressants
and other psychotropic medication use in the country.
Country, Publication
Year, Type
Depression, Initiate or
Continue AD
AD Intake by Time of
BF Switching AD Preferred or Not
Preferred AD
AD Use Postpartum
(%)
Most Common ADs
Postpartum
Treatment Co-Morbid
Anxiety
Other Psychotropic
Postpartum (%)
Denmark [17] PMH-S NS
No, but weight gain in
infant should be
monitored. Formula
can be considered.
No, if the AD is
effective and was taken
in pregnancy
Sertraline, paroxetine
/
Fluoxetine,
(es)citalopram,
fluvoxamine,
venlafaxine
4.1 [29] NA NS BZD: 1.3 [20]
AP: NA
Quetiapine: NA
Finland [22]
N-PPD
As for non-pregnant
adults, psychotherapy
is recommended for
mild symptoms
No, use of SSRI does
not prevent BF NS SSRIs
/
Fluoxetine NA NA NS BZD: 0.7–3.2 [47]
AP: NA
Quetiapine: NA
Int. J. Environ. Res. Public Health 2022,19, 1973 9 of 17
Table 2. Cont.
Country, Publication
Year, Type
Depression, Initiate or
Continue AD
AD Intake by Time of
BF Switching AD Preferred or Not
Preferred AD
AD Use Postpartum
(%)
Most Common ADs
Postpartum
Treatment Co-Morbid
Anxiety
Other Psychotropic
Postpartum (%)
Germany [26]
N-PPD
Yes, after risk–benefit
analysis for mother and
child and individual
disease history,
preference, and
availability of
alternative treatments
Yes, after risk–benefit
analysis for mother and
child NS SSRIs, tricyclics
/
NS NA NA NS BZD: NA
AP: NA
Quetiapine: NA
Italy [28]
PMH-S
Yes, after risk–benefit
analysis for mother and
child
No, use of SSRI does
not prevent BF NS NS
/
Fluoxetine 2.5–3.4 [29] NA Yes, short-term acting
BZD
BZD: NA
AP: NA
Quetiapine: NA
Latvia [48]
PMH-S
Yes, after risk–benefit
analysis for mother and
child in case of BF. For
initiation of AD, start
with lowest effective
dose.
Assess whether dosage
and regimen are
compatible with BF NS SSRIs, sertraline
/
Fluoxetine NA NA
Yes, mirtazapine or
atypical AP; quetiapine
for augmentation
therapy. Olanzapine
only at low doses. BZD
should be avoided.
BZD: NA
AP: NA
Quetiapine: NA
Malta [32]
PMH-S
Yes, after individual
risk–benefit assessment;
drug choice based on
lowest risk,
monotherapy if
possible and at the
lowest effective dose
Yes, after individual
risk–benefit assessment;
drug choice based on
lowest risk,
monotherapy if
possible, and at the
lowest effective dose,
previous response is
considered
NS
Iimipramine,
nortriptyline, sertraline
/
Citalopram, fluoxetine
NA SSRIs e.g., sertraline,
paroxetine
(unpublished data)
Short-term BZD
(caution in BF). Close
monitoring of babies
exposed to BZD via
breastmilk. Diazepam
should not be used
while BF.
BZD: NA
AP: NA
Quetiapine: NA
The Netherlands
33 PMH-S Yes, continue SSRI after
delivery Yes, BF is
recommended No, no evidence for
switching
Paroxetine, sertraline
/
Fluoxetine, citalopram 3.1 [34]Paroxetine,
citalopram,
sertraline [34]NS BZD: NA
AP: NA
Quetiapine: NA
Norway [36] PMH-S Yes, if severe after
individual risk–benefit
assessment NS No
Sertraline, paroxetine
/
Doxepin, fluoxetine,
citalopram
1.0 [37] NA NS BZD: 0.8 [37]
AP: 0.2 [37]
Quetiapine: NA
Poland [39]
PMH-S
Yes, initiate if severe
and continue to prevent
relapse.
If history of severe
depression or ongoing
mild-to-moderate
symptoms, AD should
be considered.
Yes, AD in one daily
dose before the child’s
longest
sleep, and BF is
recommended just
before AD intake
No, same treatment
pattern should
be used after delivery
Sertraline, citalopram
/
Fluoxetine NA NA NA BZD: NA
AP: NA
Quetiapine: NA
Int. J. Environ. Res. Public Health 2022,19, 1973 10 of 17
Table 2. Cont.
Country, Publication
Year, Type
Depression, Initiate or
Continue AD
AD Intake by Time of
BF Switching AD Preferred or Not
Preferred AD
AD Use Postpartum
(%)
Most Common ADs
Postpartum
Treatment Co-Morbid
Anxiety
Other Psychotropic
Postpartum (%)
Serbia [40]
N-PPD
Yes,
if severe after
individual risk–benefit
assessment
NS No Fluoxetine NA Paroxetine
(data unpublished) NS BZD: NA
AP: NA
Quetiapine: NA
Spain [41]
PMH-S
Yes, if severe after
individual risk–benefit
assessment NS NS
Nortriptyline,
sertraline,
paroxetine
/
Citalopram, fluoxetine
NA NA NS BZD: NA
AP: NA
Quetiapine: NA
United Kingdom
[44,45] PMH-S
Yes, particularly for
moderate-to-severe
depression after
discussing with the
woman of the
risk–benefit assessment
of AD; drug choice
based on lowest risk,
monotherapy if
possible and at the
lowest effective dose.
Consider risks and
benefits of BF, which
should generally be
encouraged, but
monitor baby for any
adverse effects.
Option to be discussed
with the woman, but
aim is to expose the
breastfed infant to as
few drugs as possible.
Unspecified, choice
based on prior drug
response and its safety
profile in breastfeeding.
5.5–12.9 [29,46] SSRI [49]
Yes, but do not offer
BZD except for the
short-term treatment of
severe anxiety. BZD
best avoided in BF if
possible; use drug with
shortest half-life.
BZD: NA
AP: 0.4 [46]
Quetiapine: NA
NA = not available; NS = not specified; AD = antidepressant; BF = breastfeeding; BZD = benzodiazepines; AP = antipsychotics; SAH = sedative antihistamines; PMH-S = peripartum
mental health specific.
Int. J. Environ. Res. Public Health 2022,19, 1973 11 of 17
The specific substances recommended and not recommended vary considerably be-
tween the CPGs, but taken together, sertraline (8/12 CPGs) and paroxetine (5/12 CPGs)
are the ones most commonly preferred, while fluoxetine is not preferred in most CPGs
(
8/12 CPGs
) due to its very long half-life with the risk of accumulation in the infant. Parox-
etine, citalopram, sertraline, or SSRI in general are also the antidepressants most commonly
taken by women postpartum. Fluoxetine does not rank high in drug utilization studies in
the postpartum period.
3.4. Pharmacological Interventions for Antenatal or Postpartum Comorbid Anxiety and Use of
Other Psychotropics
Treatment recommendations for comorbid anxiety are largely missing for both the
antenatal and the postpartum period (Tables 1and 2). Only seven GPGs state that ben-
zodiazepines can be offered in the case of severe anxiety during pregnancy but only for
short-term treatment. In Malta, benzodiazepines are recommended only as needed, and
the treatment of choice is augmentation with quetiapine, both during pregnancy and post-
partum. During the latter period, sedative antihistamines represent a treatment option.
In the UK, it is advised to treat comorbid anxiety with antidepressants during pregnancy
or short-term benzodiazepines, and the latter medication is discouraged at postpartum
in case of breastfeeding. The CPG in Latvia recommends treatment of comorbid anxiety
postpartum with mirtazapine or atypical antipsychotics, including olanzapine at a low
dose, while benzodiazepines should be avoided.
Prenatal use data for benzodiazepines, antipsychotics, and quetiapine specifically
are lacking for some countries, and for sedative antihistamines, data are very sparse.
During pregnancy, benzodiazepines are often used to a larger extent than antidepressants
in specific countries (i.e., Germany, Poland, Serbia, and Spain), while in Norway, the use of
benzodiazepine and sedative antihistamines is comparable (about 1%). With regard to the
use of other psychotropic medication (as an add-on) in the postpartum period, utilization
data are largely unavailable, as only the Nordic countries and the UK report postpartum use
of benzodiazepines and antipsychotics in the ranges of 0.8–3.2% and 0.2–0.4%, respectively.
4. Discussion
This review across European countries reports important gaps in the availability, agree-
ment, and up-to-date evidence-based content of CPGs for the pharmacological treatment
of peripartum depression. This may have implications in the decision making and uptake
of effective treatment among perinatal women and consequently in reducing the pervasive
costs of peripartum depression. Several of our findings are important for clinical practice
and perinatal drug research at large. First, we identified a national CPG only in 12 out of
the 48 countries in Europe, adding 6 guidelines to the latest synthesis by Molenaar et al. in
2018 [
14
]. Nevertheless, the absence of a CPG in most countries raises clear concerns about
the pharmacological management of depression in pregnant women and new mothers [
10
],
especially in countries where higher rates of peripartum depression [
50
,
51
] are paralleled by
low use of antidepressants and greater use of benzodiazepines [
24
]. Second, we found gen-
eral agreement within the CPGs in recommending psychotherapy as first-line intervention,
as well as antidepressant initiation or continuation based on psychotherapy non-response
or depression severity. However, the recommendations are sometimes unspecific and
not uniform across guidelines. Third, emerging issues and questions that are met in the
real-world practice are not covered with the latest available evidence (e.g., drug monitoring
or dose adjustments, antidepressant switching and treatment augmentation, adjuvant
strategies for comorbid anxiety, and compatibility of breastfeeding with antidepressant
treatment). Finally, the unavailability of antidepressant and other psychotropic utilization
data from pre-pregnancy through the end of the first postpartum year, especially in some
countries, impedes the evaluation of prescribers’ compliance to a CPG and calls for ad hoc
perinatal drug utilization research.
Int. J. Environ. Res. Public Health 2022,19, 1973 12 of 17
The available evidence about antidepressant safety and antidepressant effectiveness
in the context of continuation, discontinuation, or initiation is limited, especially for the
pregnancy period [
50
,
52
57
]. It is now widely acknowledged that intrauterine exposure to
SSRIs does not substantially increase the risk of congenital anomalies in offspring, while the
risk for negative longer-term developmental outcomes is less clear [
58
60
]. However, only
more recent studies have compared outcomes in offspring born to continuers versus discon-
tinuers [
61
]. Antidepressant continuation in pregnancy was found to increase the risk of
low birth weight, premature birth, or affective disorder diagnosis later in childhood
[6265]
.
Yet, the role of confounding by maternal disease severity remains an important concern in
this research. Regarding antidepressant effectiveness, a recent meta-analysis [
53
] found a
74% increased risk of depression relapse during pregnancy with antidepressant discontinu-
ation relative to continuation in pregnancy. The four included studies were, however, very
heterogeneous and adopted an oversimplified definition of antidepressant continuation
or discontinuation that did not reflect the treatment intensity, dose changes, or timing of
exposure as in real-world settings [6668].
No observational or randomized study to date has investigated the benefit of antide-
pressant initiation in pregnancy on relapse or remission of peripartum depression. The
need for clinical drug trials in pregnant and postpartum women has never been greater [
69
].
The findings from the “stop or go” randomized trial indicated no significant difference in
the risk of relapse of depression in women who tapered SSRIs with additional preventive
cognitive therapy, relative to those who continued SSRIs [
70
]. However, the study included
only 44 women, demonstrating the need for larger trials which also address the efficacy
of antidepressant initiation in pregnancy. In 2019, the Food and Drug Administration in
the US approved the first drug specifically for the treatment of postpartum depression: the
GABA-A receptor modulator brexanolone. Brexanolone is not yet approved in the EU, but
regulatory pathways have been initiated for future marketing authorization. This new drug
constitutes an important therapeutic option for women with severe postpartum depression,
but its difficult administration in terms of duration and form (i.e., intravenously) may limit
its usage. Determining the comparative effectiveness and safety of brexanolone versus any
other treatment for postnatal depression [
54
] will be crucial to inform clinical decisions
involving CPGs at an international level. Similarly, more research is needed about the com-
parative effectiveness of different pharmacological interventions versus other therapeutic
options, such as electroconvulsive therapy for treatment of severe perinatal depression.
There remains a need for more unified guidelines on the use of antidepressants to
treat peripartum depression to guide clinical decision making. However, the decision to
treat peripartum depression with antidepressants must always consider the individualized
risk–benefit profile of the medication for each woman [
54
]. Most CPGs recommend an
individualized risk–benefit assessment, which should consider the psychiatric history of
the woman, her response to prior or ongoing antidepressants, mental health outcomes
following prior attempts to discontinue the medication, the woman’s treatment preference,
and her desire to breastfeed. The antidepressant with the lowest known risk for breastfed
children in the lowest effective dose and in the lowest effective drug serum concentration
should be prescribed [
60
]. To the best of our knowledge, there is no evidence base to
discourage breastfeeding of preterm or low birth weight infants. However, caution is
needed due to the immature liver metabolic capacity in preterm infants, especially in
combination with maternal fluoxetine use, which has a long half-life and increased risk of
accumulation in the breastfed infant [
60
]. The decision making in pregnancy and while
breastfeeding could be aided by further development of patient decision aid (PDA) tools.
Early data suggest that they are acceptable to users and reduce decisional conflict [71,72].
Generally, there was satisfactory compliance in prescribing preferred antidepressants
during pregnancy (e.g., sertraline and citalopram), although exceptions were noted. Parox-
etine ranked among the most commonly used antidepressants in pregnancy in specific
countries, despite being a non-preferred antidepressant. However, we could not corrobo-
rate whether this drug choice was derived from an individualized assessment based on
Int. J. Environ. Res. Public Health 2022,19, 1973 13 of 17
maternal prior response to the drug or whether it reflects poor prescriber compliance to
the CPG. One Dutch study [
73
] found that gynecologists and midwives were aware of
the national CPG on antidepressants in pregnancy, yet only 13.9% of them adhered to
its recommendations. Efforts are, therefore, necessary to facilitate the uptake of the CPG
recommendations in routine clinical practice by all healthcare professionals involved in the
care of women with peripartum depression.
One key finding is that guidance on intervention strategies for comorbid anxiety and
advice on augmentation with antipsychotics are largely missing across the examined CPGs,
and when present, it is too unspecific with regard to drug selection and maximum permis-
sible doses. Indeed, we observed important country-specific fluctuations in the utilization
of benzodiazepines that need to be addressed. Uniform, specific recommendations for
this problem are needed for multiple reasons: (1) some women manifest active depressive
symptoms despite antidepressant treatment, and clinicians need evidence-based guidance
to treat them; (2) anxiety is a prominent symptom of severe peripartum depression [
4
]; and
(3) benzodiazepines should be used only sporadically during pregnancy or postpartum,
and alternative interventions are necessary for protracted treatments [
60
]. Yet, to date,
evidence does not exist to help make recommendations for the perinatal population, which
calls for urgent population-based perinatal drug research.
Strengths and Limitations
Several strengths and limitations need mentioning. One of the main strengths of this
synthesis is that we provided a global view of the existing CPGs across Europe. We applied
multiple search strategies, our search was not restricted to CPGs meeting the AGREE
instrument, and we applied no language restrictions, which enabled us to gather as many
CPGs as possible, including current clinical practices. Direct contact with representatives of
the COST network and experts in psychiatry and psychology allowed us to examine CPG
availability in low- and middle-income countries in Europe, which are unlikely to publish
national CPGs. Our review did not include consensus statements or expert opinion articles,
as these items only reflect individuals’ perspectives or practices. In addition, we extracted
psychotropic utilization data from the literature as a proxy of prescribers’ compliance to
their national CPGs. However, such a proxy is not ideal, and specific field studies are
necessary to accurately measure prescribers’ adherence to the CPGs [
73
]. Identification of
CPGs eligible for inclusion in the review was performed by a single author, but the final
decision for inclusion or exclusion was agreed upon by all authors. We did not assess the
quality of the included CPGs based on the AGREE instrument, and therefore, we could not
assess the degree of the evidence upon which the different CPG recommendations were
based. Lastly, our review was restricted to European countries, and so our results are not
generalizable to countries outside Europe.
5. Conclusions
Many countries in Europe do not have a CPG for pharmacological treatment of
peripartum depression, and where present, recommendations are not fully uniform and
not up to date with the latest available evidence. This review expresses the urgent need for
a harmonized, up-to-date CPG for pharmacological management of peripartum depression
and comorbid anxiety in Europe. Treatment recommendations need to be informed by
the latest available evidence and cover emerging issues that are met in the current clinical
practice. Our work is only the first step in facilitating the complex decision making in
pharmacological treatment of women with peripartum depression. Women across Europe
should be empowered to make informed, evidence-based decisions about their treatments
during pregnancy and while breastfeeding.
Author Contributions:
All authors participated in the conceptualization, methodology, review, and
editing; formal analysis, A.L.; writing—original draft preparation, A.L., S.K.-S., E.F., R.B., M.L.-v.d.B.,
C.A.W., V.B.B., K.S.V., B.M., A.F. and A.O.; data curation, A.L.; project administration, A.L. All authors
have read and agreed to the published version of the manuscript.
Int. J. Environ. Res. Public Health 2022,19, 1973 14 of 17
Funding:
This paper was supported by COST under COST Action Riseup-PPD CA18138 www.cost.eu
(access date 30 September 2021). A.L. was supported by the Norwegian Research Council (grant
number 288696). C.A.W. was funded by the UK’s National Institute for Health Research (NIHR). The
funders had no role in the analyses, interpretation of results, or the writing of this manuscript.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: All data are available online in Medline (via PubMed).
Acknowledgments:
We are grateful to all national members of Riseup-PPD COST ACTION and the
researchers and clinicians that supported our search for clinical practice guidelines. This paper is
based upon work from the COST Action Riseup-PPD CA 18138 and was supported by COST under
COST Action Riseup-PPD CA18138 www.cost.eu (access date 30 September 2021).
Conflicts of Interest: The authors declare no conflict of interest.
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Though prenatal antidepressant exposure has been associated with adverse developmental outcomes, the extent to which the effects are due to prenatal drug exposure or underlying maternal mood disturbances is unclear. This was a population-based retrospective cohort study using administrative data from British Columbia, Canada (n = 94,712). Analyses were designed to remove confounding effects of prenatal antidepressant exposure from maternal mood. First, children prenatally exposed to antidepressants were matched to unexposed children using high-dimensional propensity scores (HDPS). Second, children whose mothers had used antidepressants throughout pregnancy were compared against those whose mothers discontinued treatment. In all, 3.87% (n = 3661) of children in the overall study population were prenatally exposed to antidepressants. In both analyses, we report increased odds for lower levels of physical independence (HDPS: OR, 1.14; 95% CI, 1.00–1.30; continuers/discontinuers: OR, 1.14; 95% CI, 0.99–1.32), and higher levels of anxious behaviors (HDPS: OR, 1.30; 95% CI, 1.01–1.66; continuers/discontinuers: OR, 1.32; 95% CI, 1.01–1.72) associated with antidepressant use in pregnancy. All other relationships were not significant using these methods. Prenatal antidepressant exposure was selectively associated with worse anxious behaviors and physical independence at kindergarten age, with no effects on other developmental domains. Effects are also likely attributable to maternal mental illness severity or other unmeasured confounding factors. Selective associations between prenatal antidepressant exposure and children’s anxiety and physical independence at kindergarten were identified, with no impact on other developmental domains. Contradictory reports have emerged regarding the association of adverse child outcomes with prenatal antidepressant exposure. These inconsistencies may be due to differences in control for confounding. Effects of prenatal antidepressant exposure on anxious behaviors and physical independence are likely also attributable to severity of underlying maternal mood disorders, highlighting the importance of maternal mental health for developmental health.
Article
Objective To investigate the impact of major depressive disorder (MDD) and antidepressant medication before and during pregnancy on obstetric and neonatal outcomes. Study design A national register‐based cohort study of pregnant women born in Sweden, and their first child born in 2012-2015 (n = 262 329). Women diagnosed with MDD and who had redeemed an antidepressant one year before becoming pregnant (“before pregnancy”) and women who were diagnosed with MDD and who had redeemed an antidepressant both before and during pregnancy (“before and during pregnancy”) were compared with each other and with women who had neither been diagnosed with MDD nor been prescribed antidepressants (population controls). Results In comparison to population controls, the “before pregnancy” and the “before and during pregnancy” groups had increased likelihoods of operative childbirth (aOR = 1.19, 95% CI 1.12-1.27, aOR = 1.38, 95% CI 1.28-1.48 respectively), and with an increased likelihood for the child being admitted to a neonatal intensive care unit (NICU) (aOR = 1.51, 95% CI 1.17-1.95, aOR = 1.55, 95% CI 1.14-2.11). Children born to mothers in the “before and during pregnancy” group had an increased likelihood of preterm birth (aOR = 1.72, 95% CI 1.52-1.95,), while children to mothers in the “before pregnancy” group had an increased likelihood of low birthweight (aOR = 1.15, 95% CI 1.00-1.33) compared to population controls. Women in the “before and during pregnancy” group had an increased likelihood for hyperemesis during pregnancy (OR = 1.93, 95% CI = 1.60-2.32), having an operative childbirth (OR = 1.17, 95% CI = 1.06-1.29) or a preterm birth (OR = 1.53, 95% CI = 1.28-1.81) compared to the “before pregnancy” group. Conclusions Women with MDD and antidepressant medication prior to becoming pregnant are at increased risk for adverse obstetric and neonatal outcomes compared to women without an MDD. Continuation of antidepressant medication during pregnancy somewhat increased the risk for adverse obstetric and neonatal outcomes.