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Abstract and Figures

Background Non-invasive brain stimulation (NIBS) techniques have been suggested as alternative treatments to decrease depression symptoms during the perinatal period. These include brain stimulation techniques that do not require surgery and that are nonpharmacological and non-psychotherapeutic. NIBS that have showed antidepressant effect so far include repetitive transcranial magnetic stimulation (rTMS), transcranial electric stimulation (TES) and electroconvulsive therapy (ECT). Objectives This systematic review aims to summarize evidence on NIBS efficacy, safety and acceptability in treating peripartum depression (PPD). Methods We included randomized, non-randomized and case reports, that used NIBS during pregnancy and the postpartum. The reduction of depressive symptoms was the primary outcome and neonatal safety was the co-primary outcome. Results: rTMS shows promising results for the treatment of PPD, with clinically significant decreases in depressive symptoms between baseline and end of treatment and overall good acceptability. Although the safety profile for rTMS is adequate in the postpartum, caution is warranted during pregnancy. In TES, evidence on efficacy derives mostly from single-arm studies, compromising the encouraging findings. Further investigation is necessary concerning ECT, as clinical practice relies on clinical experience and is only described in low-quality case-reports. Limitations The reduced number of controlled studies, the lack of complete datasets and the serious/high risk of bias of the reports warrants cautious interpretations. Conclusions and implications Existing evidence is limited across NIBS techniques; comparative studies are lacking, and standard stimulation parameters are yet to be established. Although rTMS benefits from the most robust research, future multicenter randomized clinical trials are needed to determine the position of each NIBS strategy within the pathways of care.
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Journal of Psychiatric Research 140 (2021) 443–460
Available online 8 June 2021
0022-3956/© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
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Review article
Efcacy of non-invasive brain stimulation in decreasing depression
symptoms during the peripartum period: A systematic review
Francisca Pacheco
a
, Raquel Guiomar
b
, Andre R. Brunoni
c
, Rachel Buhagiar
d
,
Olympia Evagorou
e
, Alba Roca-Lecumberri
f
, Anna Poleszczyk
g
,
Mijke Lambregtse-van den Berg
h
, Rafael A. Caparros-Gonzalez
i
, Ana Fonseca
a
,
b
, Ana Os´
orio
j
,
Mahmoud Soliman
k
, Ana Ganho-´
Avila
b
,
*
a
University of Coimbra, Faculty of Psychology and Educational Sciences, Coimbra, Portugal
b
Center for Research in Neuropsychology and Cognitive-Behavior Interventions, Faculty of Psychology and Educational Sciences, University of Coimbra, Coimbra,
Portugal
c
Department of Internal Medicine and Psychiatry, Faculdade de Medicina da Universidade de S˜
ao Paulo, S˜
ao Paulo, Brazil
d
Mental Health Services, Malta
e
University General Hospital of Alexandroupolis, Department of Psychiatry, Greece
f
Perinatal Mental Health Unit, Psychiatry and Clinical Psychology Service, Hospital Clinic de Barcelona, Barcelona, Spain
g
Centre Hospitalier Sainte Marie, Pˆ
ole Est, Nice, France
h
Departments of Psychiatry and Child & Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
i
University of Granada, Faculty of Health Sciences, Department of Nursing, Granada, Spain
j
Graduate Program on Developmental Disorders, Center for Biological and Health Sciences, Mackenzie Presbyterian University, S˜
ao Paulo, Brazil
k
Department of Radiology, Charit´
e - Universit¨
atsmedizin Berlin, Berlin, Germany
ARTICLE INFO
Keywords:
Peripartum
Perinatal
Depression
Non-invasive brain stimulation
Systematic review
ABSTRACT
Background: Non-invasive brain stimulation (NIBS) techniques have been suggested as alternative treatments to
decrease depression symptoms during the perinatal period. These include brain stimulation techniques that do
not require surgery and that are nonpharmacological and non-psychotherapeutic. NIBS with evidence of anti-
depressant effects include repetitive transcranial magnetic stimulation (rTMS), transcranial electric stimulation
(TES) and electroconvulsive therapy (ECT).
Objectives: This systematic review aims to summarize evidence on NIBS efficacy, safety and acceptability in
treating peripartum depression (PPD).
Methods: We included randomized, non-randomized and case reports, that used NIBS during pregnancy and the
postpartum. The reduction of depressive symptoms and neonatal safety were the primary and co-primary out-
comes, respectively.
Results: rTMS shows promising results for the treatment of PPD, with clinically significant decreases in depressive
symptoms between baseline and end of treatment and overall good acceptability. Although the safety prole for
rTMS is adequate in the postpartum, caution is warranted during pregnancy. In TES, evidence on efcacy derives
mostly from single-arm studies, compromising the encouraging ndings. Further investigation is necessary
concerning ECT, as clinical practice relies on clinical experience and is only described in low-quality case-reports.
Limitations: The reduced number of controlled studies, the lack of complete datasets and the serious/high risk of
bias of the reports warrant cautious interpretations.
Conclusions and implications: Existing evidence is limited across NIBS techniques; comparative studies are lacking,
and standard stimulation parameters are yet to be established. Although rTMS benets from the most robust
research, future multicenter randomized clinical trials are needed to determine the position of each NIBS strategy
within the pathways of care.
* Corresponding author. Center for Research in Neuropsychology and Cognitive-Behavior Interventions, Faculty of Psychology and Educational Sciences of the
University of Coimbra, Rua do Col´
egio Novo, 3001-802, Coimbra, Portugal.
E-mail address: ganhoavila@fpce.uc.pt (A. Ganho-´
Avila).
Contents lists available at ScienceDirect
Journal of Psychiatric Research
journal homepage: www.elsevier.com/locate/jpsychires
https://doi.org/10.1016/j.jpsychires.2021.06.005
Received 21 January 2021; Received in revised form 4 May 2021; Accepted 4 June 2021
Journal of Psychiatric Research 140 (2021) 443–460
444
1. Introduction
1
Peripartum Depressive Disorder (PPD) is a Major Depressive Disor-
der (MDD) with the onset of the depressive symptoms occurring during
pregnancy or within 12 months postpartum (Wisner et al., 2013; Woody
et al., 2017). The pooled prevalence of PPD is 11.9%, representing a
major public health issue (Woody et al., 2017; Meltzer-Brody et al.,
2013). PPD affects mothers and infants, leading to adverse outcomes in
pregnancy (Grote et al., 2010) and in the postpartum (Field, 2010;
Slomian et al., 2019).
Decision-making about PPD treatment must be dened on a case-by-
case basis, according to individual characteristics (e.g., severity of
symptoms, willingness to use medication, and previous antidepressant
response), the best clinical evidence, the available treatments, and
respecting womens preferences (Charlton et al., 2014; Fonseca et al.,
2020). Pharmacotherapy and psychotherapy are rst- and second-line
treatments in PPD (Bledsoe and Grote, 2006) and both present limita-
tions. Whereas antidepressants lack investigation (Howard et al., 2020)
and pose risks for fetal development (Molenaar et al., 2018), psycho-
therapy is not always effective and is a costly treatment (van Ravesteyn
et al., 2017). New alternatives are thus needed to ensure universal
high-quality perinatal mental health.
Non-invasive brain stimulation (NIBS) is one of the fastest-growing
elds in medicine (Borrione et al., 2020) and refers to a set of tech-
niques used to modulate brain activity using non-implantable methods
(Albizu et al., 2019).
rTMS impacts synaptic transmission through patterned energy that
changes neurons activity and connectivity (George and Aston-Jones,
2010) with an immediate local and remote effect (Terranova et al.,
2019). The most studied condition for its therapeutic application is
unipolar depression (Lefaucheur et al., 2020) with two systematic re-
views concluding for rTMS efcacy, acceptability and tolerability in PPD
(Cole et al., 2019; Ganho-´
Avila et al., 2019).
Theta burst stimulation (TBS) is a shorter form of rTMS that can be
administered through continuous or intermittent protocols (cTBS and
iTBS, respectively; Di Lazzaro et al., 2008), addressing the
time-consuming issue associated with rTMS (Blumberger et al., 2018).
Transcranial Electrical Stimulation (TES) techniques involve the
application of a low-intensity electrical current. Transcranial direct
current stimulation (tDCS) applies an electric current between two
electrodes placed over the scalp, inducing cortical excitability (Merza-
gora et al., 2010), facilitating or inhibiting the synaptic transmission and
the frequency of action potentials during endogenous neuronal ring
(Brunoni et al., 2012). tDCS is a low-cost treatment that uses a constant
direct current (Bennabi and Haffen, 2018), shows favorable results in
MDD and has a good safety prole (Lefaucheur et al., 2017). To our
knowledge, there is no review on the effectiveness of tDCS in PPD,
despite its promising features for the peripartum, in particular, at-home
protocols (Alonzo et al., 2019; Alonzo and Charvet, 2016). Other TES
techniques of interest are transcranial alternating current stimulation
(tACS), that in MDD uses an oscillating sinusoidal current to target alpha
oscillations (Antal et al., 2008; Alexander et al., 2019); and trigeminal
nerve stimulation (TNS) that applies electric current over a branch of the
trigeminal nerve, allowing for the propagation of the stimuli to brain
areas involved in mood regulation (Chiluwal et al., 2017; Shiozawa
et al., 2015).
Electroconvulsive therapy (ECT) is recommended for severe
psychiatric symptoms, including depression with psychosis, suicidal
ideation, and mania, when patients have had previous positive response
to ECT or/and are non-responsive to medication (American Psychiatric
Association Committee on Electroconvulsive Therapy, 2001). Used as a
tertiary treatment for severe MDD, ECT involves a generalized
controlled seizure, produced by a series of short electric current bursts
delivered through electrodes to the brain (Mutz et al., 2019). ECT seems
to be more efcacious and safer than medication for severely ill preg-
nant women and in minimizing fetal exposure to psychotropics (Amer-
ican Psychiatric Association Committee on Electroconvulsive Therapy,
2001). To address the adverse effects that have been reported, additional
obstetric care and close maternal and fetal monitoring is added during
ECT treatments in pregnancy (Coshal et al., 2019). Although women in
the postpartum period seem to be those who most benet from ECT
treatments (Rundgren et al., 2018), recent literature suggests the asso-
ciation between ECT and memory impairments, lower rates of treatment
response and remission, and longer treatment courses in young,
educated women with no history of suicidal self-injury (Li et al., 2020).
Evidence concerning NIBS in PPD is promising but scattered.
Therefore, this study aimed to synthesize knowledge about its use from
pregnancy to postpartum. We aimed to clarify the efcacy of NIBS in
decreasing peripartum depressive symptoms (as a stand-alone, add-on
therapy or augmentation intervention to antidepressants) when
compared to pharmacotherapy, psychological interventions, other brain
stimulation techniques, or no treatment.
2. Methods
This systematic review aimed at gathering evidence about the ef-
cacy, safety, and acceptability of NIBS in PPD, by addressing the
following critical questions:
i) What is the evidence of efcacy in reducing depressive symptoms
during the peripartum period, across NIBS?
ii) What is the safety prole of each NIBS technique regarding
women, fetuses and neonatal outcomes?
iii) What is the level of acceptability of NIBS for women, as measured
by dropout rates?
iv) What is the impact of NIBS in the neuropsychological functioning
of women?
2.1. Protocol and registration
This systematic review was registered in PROSPERO
(CRD42020153132) and was conducted under COST Action RISEUP-
PPD (CA18138).
2.2. Literature review and search methods
Data search was conducted independently by two authors (FP e RG)
from inception to October 2019 in Pubmed/Medline, PsycINFO, Web of
Science, and Lilacs for peer-reviewed studies and for unpublished
studies in the Networked Digital Thesis and Dissertations, for the
available publications and reports in English, French, Spanish, or Por-
tuguese. Manual verication of the list of references was also conducted
by the same authors and disagreements were resolved with a third
author in agreement to their specic expertise (AGA, AP, MLvdB). Ac-
cording to the Methodological Expectations of Cochrane Intervention
Reviews (MECIR), a search update was performed in May 2020. The
complete search strategy can be consulted in Supplementary Materials.
2.3. Eligibility criteria
Randomized clinical trials (RCT) and non-randomized studies (NRS)
were included, enrolling women diagnosed with PPD at the start of
1
Abbreviations: MDD: major depressive disorder; PPD: peripartum depres-
sion disorder; NIBS: noninvasive brain stimulation; rTMS: repetitive trans-
cranial magnetic stimulation; TES: transcranial electrical stimulation; tDCS:
transcranial direct current stimulation; TBS: theta burst stimulation; ECT:
electroconvulsive therapy; tACS: transcranial alternating current stimulation;
TNS: trigeminal nerve stimulation; RCT: randomized clinical trials; NRS: non-
randomized studies.
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
445
treatment, according to the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5; American Psychiatric Association, 2013) or the In-
ternational Statistical Classication of Diseases and Related Health
Problems (ICD-10; World Health Organization, 2004).
The studiesparticipants should be at least 18 years old and have
received rTMS, iTBS, tDCS, tACS, TNS or ECT as a stand-alone, add-on or
augmentation treatment, across the peripartum period. Eligible com-
parators were other types of brain stimulation, psychotherapy, phar-
macotherapy, or no treatment.
2.4. Data extraction and outcome measures
Titles and abstracts were screened by two independent researchers
using Ryyaan (Ouzzani et al., 2016) to identify studies that met the in-
clusion criteria, with substantial inter-rater reliability (k =0.80) (Landis
and Koch, 1977). Disagreements were solved through in-depth discus-
sions until consensus was reached. Data for study design, study popu-
lation, demographic and baseline characteristics, type of intervention
and comparator, and outcomes, were extracted from the full-text reports
by one researcher and reviewed by other three. Reduction of depressive
symptoms was the primary outcome, as assessed by all versions of the
Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960), the
Edinburgh Postnatal Depression Scale (EPDS) (Cox and Holden, 2003),
the Inventory of Depressive Symptomatology-Self-Report (IDS-SR)
(Rush et al., 1986), the Clinical Global Impressions scales (CGI) (Busner
and Targum, 2007; Guy, 1976), the MontgomeryAsberg Depression
Rating Scale (MADRS) (Montgomery and Asberg, 1979), and the Beck
Depression Inventory (BDI) (Beck et al., 1961). Neonatal safety in-
dicators were primary co-outcomes.
The response rate, remission status, time to response, safety for
mothers, acceptability measures and neurocognitive assessment mea-
sures were secondary outcomes. In case of missing or unclear data, two
attempts were made to contact the original authors by email, in a two-
week interval.
2.5. Qualitative and quantitative data synthesis
The synthesis of results was conducted considering efcacy,
acceptability (according to the dropout rates), adverse effects, and
neonatal safety outcomes.
2.6. Risk of bias assessment
To assess the risk of bias (RoB) in RCTs, we used the Cochrane
Fig. 1. Flow diagram of the study selection procedure according to PRISMA, 2009
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
446
Collaborations tool (Higgins et al., 2011). For open-label studies, we
used the Risk of Bias in Non-Randomized Studies of Interventions
Robins-I seven domains (Sterne et al., 2016) and robvis for visualization
(McGuinness and Higgins, 2020). To assess RoB in case reports, we
adapted the 20-criterion quality appraisal checklist from the Institute of
Health Economics (IHEs) (Guo et al., 2016) and used 12 of the available
criteria. The RoB assessment was performed by one rater and checked by
two others. Discrepancies were fully discussed and a nal judgment of
overall RoB was agreed.
3. Results
3.1. Search results
We identied 327 articles, as summarized in Fig. 1. The single grey
literature report found was a masters thesis (Myczkowski, 2009)
describing the same data later published as a peer-reviewed manuscript
(Myczkowski et al., 2012) therefore, we assumed one report. Despite the
planned search update to occur in May 2020, due to the update of the
PUBMED search engine, the previous search strategy was not repro-
ducible. Therefore, a manual search was conducted, and three new ar-
ticles were found. During the screening of the title and abstracts of these
new articles, one of the reports was excluded and two were included.
3.2. Synthesis of the extracted data
3.2.1. Description of the included studies
Fifty-three studies were included, corresponding to 54 reports (20
rTMS one of which using rTMS followed by ECT [Gahr et al., 2012], 28
ECT, one iTBS, three tDCS, one tACS and one TNS.
3.2.1.1. Repetitive transcranial magnetic stimulation. Sixteen rTMS/iTBS
studies started treatment between the rst and the third trimesters of
pregnancy of which, two continued the treatment after delivery (Burton
et al., 2014; Tan et al., 2008). Five studies started treatment only in the
postpartum period (Brock et al., 2016; Cox et al., 2020; Garcia et al.,
2010; Myczkowski et al., 2012; Odgen et al., 1999).
MDD or Major Depressive Episode (MDE) were the most common
diagnosis in studies conducted during pregnancy and only two case
studies described Bipolar Depression and Anxious Depression. rTMS
studies in the postpartum period included only women initially diag-
nosed with MDD or MDE in the postpartum. In the RCT (Myczkowski
et al., 2012), besides MDE, three patients in the active group and two
patients in the sham group were found to be experiencing their rst
bipolar depressive episode.
In pregnancy, the rst rTMS studies used a single-arm design, applied
stimulation over the right or left dorsolateral prefrontal cortex (DLPFC)
and used frequencies between 1Hz or 25Hz across 1820 sessions at
100% motor threshold (MT; Kim et al., 2011; Sayar et al., 2014; Tarhan
et al., 2012). The RCT by Kim et al. (2018) replicated Kim et al. (2011)
single-arm parameters.
Individual case studies and case series applied stimulation over left,
right or left and right DLPFC, frequencies varied between 1Hz and 25Hz
at 90120% MT and the number of sessions was also variable, ranging
between 8 and 50. Zhang and Hu (2009) and ¨
Ozten et al. (2013) did not
offer information about the stimulation parameters. The single iTBS
study available (Trevizol et al., 2019) applied triplet 50Hz bursts,
repeated at 5Hz (2s on and 8s off), with a total of 600 pulses (3min, 9s)
per session during 20 sessions, using 120% of the motor threshold.
Across studies, concomitant medication, was allowed if stable, except in
two studies reporting no use of medication (Cohen et al., 2008; Nahas
et al., 1999). Three participants from two studies completed their rTMS
treatment while in psychotherapy (Ferr˜
ao et al., 2018; ¨
Ozten et al.,
2013).
During the postpartum period, all studies targeted the left DLPFC.
The RCT applied 5Hz over 20 sessions (Myczkowski et al., 2012),
single-arm studies applied 10Hz over 20 sessions (Cox et al., 2020;
Garcia et al., 2010) or 11 sessions (Brock et al., 2016). The only case
report included applied 20Hz over 13 sessions (Ogden et al., 1999).
Concomitant medication was administered in the RCT (clonazepam;
Myczkowski et al., 2012) and in the case report (risperidone; Ogden
et al., 1999 (see Table 1).
3.2.1.2. Transcranial electrical stimulation. The primary diagnosis across
the four TES studies was MDD with all patients starting stimulation
during pregnancy, varying across trimesters. We identied one pilot
RCT (Vigod et al., 2019), one single-arm study (Palm et al., 2017) and
one case report using tDCS (Sreeraj et al., 2016). tDCS studies applied
stimulation to the DLPFC, with the anode placed over the F3 and the
cathode over the F4 (1020 international system for EEG placement;
Jasper, 1958), using the same current intensity (2 mA). Stimulation was
applied once or twice daily during 1030 sessions. TNS and tACS were
described in two case studies (Trevizol et al., 2015; Wilkening et al.,
2019, respectively). Wilkening et al. (2019) applied Gamma-tACS over
nine sessions for 20min at 40Hz, completing 48000 cycles, at 2 mA
range, and offset at 1 mA without ramp-in/ramp-out. The electrodes
were placed over the F3 and the F4 positions. The case study by Trevizol
(2015), applied TNS for 10 sessions of bilateral stimulation at 120Hz,
over the supraorbital trigeminal branches (V1). None of the TES studies
administered concomitant medication (see Table 2).
3.2.1.3. Electroconvulsive therapy. The 28 ECT reports were case
studies, for a total of 25 pregnant and 13 postpartum women. Two re-
ports described ECT treatments during the rst trimester, 19 during the
second and third trimesters, and ve during the rst 12 months post-
partum. Six reports do not detail when treatment was delivered. The rst
report using ECT in PPD during pregnancy dates from 1984 and refers to
a woman in her second trimester that received ECT unilaterally to the
non-dominant hemisphere for eight sessions (Wise et al., 1984). No
further information regarding stimulation parameters was available. In
the following years, several published reports described ECT treatments
in pregnant women diagnosed with PPD with psychotic features, peri-
partum depressive symptoms, severe depression and bipolar depression.
In the second trimester of pregnancy, ECT studies used bilateral
stimulation (with seizure duration between 17s and 186s, across 910 in
the rst trimester), or unilateral right and bifrontal montages (with
seizure durations between 20s and 201s), across 715 sessions. ECT
treatments delivered in the third trimester, placed the electrodes bilat-
erally over the temporal, frontal or frontotemporal regions, or unilat-
erally at the right hemisphere. One report did not detail the placement of
the electrodes (Rineh et al., 2020). The number of sessions per treatment
ranged from 5 to 9 and the seizure duration was established between 37s
and 90s.
Whereas in some ECT reports there was a lack of information con-
cerning medication, for the majority ECT was applied in the context of
severe psychiatric disorder not responding to previous pharmaco-
therapy, or to pharmacotherapy with one course of rTMS. Frequently it
was not clear if ineffective pharmacologic treatment was maintained
during ECT. The medication used during ECT included uoxetine and
duloxetine. Across ECT reports during pregnancy, treatment was
sometimes offered as rst-line treatment (DeBattista et al., 2002; Mal-
etzky et al., 2004; Salzbrenner et al., 2011; Rineh et al., 2020; Wise et al.,
1984; De Asis et al., 2013).
In the postpartum period, seven reports were published, describing
13 case studies where ECT was used to treat severe PPD, with and
without psychotic features. Frequently reports are not clear whether the
ineffective pharmacologic treatment was maintained (for exceptions see
Forray and Ostroff (2007) and Levy et al. (2015)). Lorazepam was
stopped before ECT in Strain et al. (2012), and uvoxamine and al-
prazolam were stopped before ECT in Kisa et al. (2005). Often, the exact
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
447
time when ECT treatment was started, within the postpartum period,
was not mentioned. However, for the reports that offer this information,
the treatment started between week six and month ve postpartum
(Robinson and Stewart, 1986; Kisa et al., 2005; Forray and Ostroff,
2007; Strain et al., 2012). The use of ECT in the postpartum was
consistently preceded by failure of pharmacologic treatment and wors-
ening of the patients clinical status.
ECT in the postpartum, was delivered for 6 to 29 sessions, and a
continuation phase was performed in Forray and Ostroff (2007). To be
effective, the duration of seizures was indicated in two studies to be
greater than or equal to 15s (Levy et al., 2015), or at least 20s (Forray
and Ostroff, 2007; Kisa et al., 2005) with postictal suppression. From the
few detailed studies, the montage used was either bilateral, bifrontal, or
right unilateral. The width of the stimulus used was either the standard
brief pulse of 1.0 ms or the ultra-brief pulse of 0.3 ms (see Table 3).
3.2.2. Efcacy
The available data regarding the reduction of depressive symptoms
was extracted from the scores according to the endpoints. However, the
per-protocol dened time-points for data extraction was not accom-
plished due to lack of available information. Therefore, to assess the
efcacy of rTMS, TES, and ECT, we limited data extraction to baseline
and end of treatment (Table 4).
Because the denition for treatment response was distinctive across
Table 1
Characteristics of the included rTMS studies.
Study Study
design
# participants Concomitant
medication
Trimester at start
of stimulation
Stimulation
site
Frequency
(Hz)
# pulses/
session
Inter event
interval (s)
Intensity
(% MT)
#
sessions
rTMS-pregnancy
Burton et al.,
2014*
Case
report
1 Yes First Bilateral
DLPFC
10 (left) N.R. N.R. 110 21
1 (right)
Cohen et al.
(2008)
Case
report
1 No First Right DLPFC 1 1600 N.R. 100 1
Ferr˜
ao and
Silva (2018)
Case
series
3 Yes First Left DLPFC 10 3000 N.R. 120 50,
38,40
1 First Right DLPFC 1 1800 N.R. 120 20
Gahr et al.
(2012)
Case
report
1 Yes Second Left DLPFC 15 2970 2s on, 8s off 110 24
Kim et al.
(2018)
RCT 22 (11 active
+11 sham)
Yes Second and third Right DLPFC 1 900 60s on, 60s
off
100 20
Kim et al.
(2011)
Single-
arm
10 Yes Second to third Right DLPFC 1 300 60s on, 60s
off
100 20
Klirova et al.
(2008)
Case
report
2 Yes Second Left DLPFC 20 2000 2.5s on, 30s
off
100 15
Third Right DLPFC 1 300 60s on, 60
off
100 15
Nahas et al.
(1999)
Case
report
1 No Second Left
Prefrontal
5 N.R. 5s on, 25s
off
100 9
¨
Ozten et al.
(2013)
Case
report
1 No Second Left DLPFC 25 1000 2s on, 30s
off
N.R. 76
Sayar et al.
(2014)
Single-
arm
30 Yes First and third Left DLPFC 25 1000 2s on, 30
off
100 18
Tan et al.,
2008*
Case
report
1 No First Left DLPFC 25 50 2s on, 28s
off
110 77
Tarhan et al.
(2012)
Single-
arm
7 Yes N.R. Left DLPFC 25 1000 2s on, 30s
off
100 18
Trevizol et al.
(2019) **
Case
report
1 No Third Left DLPFC triplet 50 Hz
bursts,
repeated at 5
Hz
600 2s on; 8 off 120 20
Xiong et al.
(2018)
Case
report
1 Yes Second Bilateral
DLPFC
10 (left) 4000 4s on,16s
off
120 41
1 (right) 900 300s on,
60s off
Zhang et al.
(2010)
Case
report
1 No 14 weeks of
gestation
Left DLPFC 1 1200 20s off 90 14
Bilateral
DLPFC
1 1200 20s off 90 14
Bilateral
DLPFC
1 1200 20s off 90 8
Zhang and Hu
(2009)
Case
series
3 N.R. N.R. N.R. N.R. N.R. N.R. N.R. N.R.
rTMS-postpartum
Brock et al.
(2016)
Single-
arm
19 No N.R. Left DLPFC 10 3000 75s on, 26
off
120 11
Cox et al.
(2020)
Single-
arm
6 No 2 weeks to 9
months
postpartum
Left DLPFC 10 3000 4s on, 26
off
120 20
Garcia et al.
(2010)
Single-
arm
9 No 1 month to 12
months
postpartum
Left DLPFC 10 3000 75s on, 26
off
120 20
Myczkowski
et al. (2012)
RCT 14 (7 active +
7 sham)
Yes 12 months
postpartum
Left DLPFC 5 1250 25s on, 20s
off
120 20
Odgen et al.
(1999)
Case
report
1 Yes N.R. Left DLPFC 20 1200 30s on, 28
off
100 13
Note. *Applied stimulation during pregnancy and continued in the postpartum period. **Used iTBS). iTBS =intermittent theta burst stimulation. rTMS =repetitive
transcranial magnetic stimulation. DLPFC =dorsolateral prefrontal cortex. MT =motor threshold. N.R. =Not reported.
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
448
studies, we adopted denitions hierarchically: at least 50% reduction of
the baseline score, followed by at least a 30% reduction of the baseline
score. Whenever none of these denitions was available, we used the
original authorsprimary denition.
Concerning rTMS studies during pregnancy, and considering only
study completers, in the RCT, 81.8% of the participants in the active
group showed response to treatment, of whom 27.7% achieved clinical
remission. In the sham group, 45.5% showed response to treatment and
18.8% remitted (Kim et al., 2018). In Kims single-arm study (2011),
70% of the patients responded and 30% reached clinical remission.
Sayars single arm (2014), showed slightly lower rates, with 38.8% re-
sponders and 61.1% remitted. Although Tarhen et al. (2012) did not
provide the mean scores, the authors reported 71.4% responders 71.4%
and 28.6% remitted. Regarding case reports, 100% of the patients were
responders and 64.3% remitted. Garh et al. (2012) and Zhang and Hu
(2009) did not report the scores at baseline and at the end of treatment
but reported treatment response or signicant symptoms relief after
treatment.
In the postpartum period, Myczkowski et al. (2012) did not report
the number of participants that responded and/or remitted, although
the mean difference between baseline and posttreatment HDRS-21 score
was greater in the active group (MD =10.72) than in the sham group
(MD =4.9). Brock et al. (2016) single-arm study, reported that 73.7% of
the participants achieved clinical remission and Cox et al. (2020) re-
ported that 33.3% responded to treatment 66.6% achieved remission
(66.6%). In Garcia et al. (2010), 88,90% women achieved clinical
remission. The single case report available in the postpartum period
reported clinical remission (Odgen et al., 1999).
In TES studies, the RCT showed the antidepressant effect of tDCS
(Vigod et al., 2019). In fact, although the group difference was not
statistically signicant, the differences from baseline to the end of
treatment in the mean MADRS score was higher for the active group
(MD =11.7; mean scores: baseline 23.5 [SD =5.15]; post-treatment
11.4 [SD =7.11]) than for the sham group (MD =11.4; mean scores:
baseline 26.8 [SD =7.48]; post-treatment: 15.8 [SD =7.65]). Moreover,
post-treatment assessments indicated remission in 37.5% of the partic-
ipants in the active group versus 22.2% in the sham condition. In Palm
et al. (2017), two out of three women completed the treatment, and one
achieved remission. Finally, all TES case studies reported clinical
remission.
Out of 28 ECT studies in pregnancy, only seven offered the exact
individual data before and after treatment with six patients responding
to treatment and six achieving remission. Similarly, in the postpartum,
only three studies out of seven offered individual data and all reported
treatment response and symptoms remission.
3.2.3. Safety
Safety for mothers and infants is summarized in Table 5. Apgar
scores (a measure of the newborn physical condition immediately after birth)
were reported when intermediate (seven or below seven; American
Academy of Pediatrics et al., 2006).
Regarding rTMS safety in pregnancy, the RCT by Kim et al. (2018)
reported three preterm births in the active group versus none in the
sham group. Across studies, the most common side effect reported by
mothers was headache, particularly during the rst 10 sessions of
treatment (36.4%) for women in the active group versus 9.1% for
women in the sham group (Fishers Exact, p =.311). From session 10
onwards, headache was reported by 9.1% of women in the active group
versus 0% in the sham group (Fishers Exact, p =1.00). Dizziness,
nausea, site pain, supine hypotension, jaw pain, and eye twitch were
also reported but no signicant group differences were found (Kim et al.,
2018).
None of the rTMS single-arm studies reported information about
neonatal safety. The adverse effects for mothers included mild headache
and supine hypotension (Kim et al., 2011), and facial muscles contrac-
tion (Sayar et al., 2014). In Tarhan et al. (2012) no side effects were
reported by participants, and the treatment was considered
well-tolerated.
As for the case studies in rTMS, three did not offer information
concerning neonatal safety (Cohen et al., 2008; Gahr et al., 2012; Nahas
et al., 1999). Of the remaining, 18.35% of the births were preterm
Ferr˜
ao and Silva, 2018; Klirova et al., 2018; Tan et al., 2008) and one
baby registered an Apgar score below seven (Ferr˜
ao and Silva, 2018).
Pain/discomfort at the application site, transient difculty in concen-
tration and sore throat (Ferr˜
ao and Silva, 2018), and tension in the
abdominal muscles at the pelvic line (attributed to anxiety) (Nahas et al.,
1999) were the adverse effects of rTMS reported during pregnancy.
During the postpartum period, the RCT (Myczkowski et al., 2012)
reported no signicant side effects. However, two participants com-
plained of minor scalp discomfort during the session and/or mild
headache immediately after stimulation. Brock et al. (2016) reported no
serious adverse events. In the remaining single-arm studies, headache
and scalp discomfort (Cox et al., 2020), and treatment site pain and
facial stimulation (Garcia et al., 2010) were also reported. Ogden et al.
(1999) did not provide information concerning safety.
In TES studies, the RCT by Vigod et al. (2019) was the single study
reporting information about neonatal safety with one preterm birth
occurring in the tDCS group. Minor transient side effects were reported
by women in 17.7% of the sessions in the active group versus 4.7% in the
sham-control (p =.001). The most common side effect was buzzingor
tinglingat the electrode site, reported in 7.3% of the active tDCS
sessions versus 0% in the sham-control (p =.003). In the single-arm
study, tDCS was considered well-tolerated and no adverse effects
occurred (Palm et al., 2017). Two case reports described phosphenes
(Sreejaj et al., 2016; Wilkening et al., 2019), and one described transient
mild burning sensations at the site (Sreejaj et al., 2016). Trevizol et al.
(2015) did not report adverse effects in mothers but stated no side effects
to the newborn.
After ECT sessions, several adverse effects potentially associated
with the treatment were reported in pregnant women, such as pelvic
Table 2
Characteristics of the included TES studies.
Study Study
design
# participants Concomitant
treatment
Trimester at start of
stimulation
Anode Cathode Current intensity #
sessions
Palm et al., 2017* Single-arm 3 No First, second and third F3 F4 2 mA 30
Sreeraj et al., 2016* Case report 1 No First F3 F4 2 mA 10
Vigod et al., 2019* RCT 20 (10 active +10
sham)
No Second to third F3 F4 2 mA 15
Wilkening et al.,
2019**
Case report 1 No First F3 F4 40Hz at 2 mA
range
9
Trevizol et al.,
2015***
Case report 1 No Second to third supraorbital
trigeminal
branches (V1)
bilaterally
120 Hz 10
Note. *Used tDCS. **Used TNS.*** Study that used tACS. TES =transcranial electric current stimulation. tDCS =transcranial direct current stimulation. tACS =
transcranial alternating current stimulation. TNS =trigeminal nerve stimulation.
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
449
Table 3
Characteristics of the included ECT studies.
Study Study
design
#participants Concomitant
treatment
Trimester
at start of
stimulation
Electrode
placement:
Stimulus
parameters
Anesthetic used Seizure duration #sessions
ECT-pregnancy
Bhatia et al.
(1999)
Case
report
2 Yes Third Bilateral N.R. thiamylal,
succinylcholine
and curare
3739 s 6
No Third Bilateral N.R. Methohexital and
succinlylcholine
67 s 5
Bozkurt
et al.
(2007)
Case
report
1 No Second Bilateral N.R. Thiopental N.R. 13
Brown et al.
(2003)
Case
report
1 No Second N.R. N.R. tiopental
succinylocholine
N.R. 8
Ceccaldi
et al.
(2008)
Case
report
1 N.R. Second N.R. N.R. etomidate,
propofol,
succamethonium
N.R. 9
De Asis et al.
(2013)
Case
report
1 No Second Unilateral
(Right)
N.R. methohexital +
succinylcholine,
methohexital
replaced with
propofol because
of fetal
bradycardia
62201 s 14
DeBattista
et al.
(2003)
Case
report
1 No Second Bilateral 45% maximum
setting for each
treatment
rst two:
thiopental
succinylcholine
for the remaining:
thiopental was
replaced with
etomidate (to
increase seizure
duration)
1st
session:22s,2nd:18s,3rd
36s, the rest not
described
5
Erturk et al.
(2020)
Case
report
1 Yes Second - Frontal
placements
N.R. thiopental (300
mg) and
rocuronium (30
mg)
N.R. 10
Gahr et al.
(2013)
Case
report
1 Yes Second Unilateral
(Right)
stimulus
intensity
between 30 and
65% of max.
stimulator
output
alfentanil
+propofol +
succinylcholine
2132 15
Gonzales
et al.
(2014)*
Case
report
1 Yes Second Unilateral
(right)
N.R. N.R. N.R. 10
Yes Postpartum Unilateral
(right)
N.R. N.R. N.R. 12
Kasar et al.
(2007)
Case
report
1 No Third Bilateral
frontotemporal
suprathreshold
stimulus dose of
126 mC(rst);
108 mC 4th
Propofol and
succinylcholine
N.R. 4
Livingston
et al.,
1994*
Case
report
1 Yes Third Bilateral N.R. N.R. Target duration 6090s 8 during
pregnancy,
continued
during
postpartum
Maletzky
(2004)
Case
report
4 No N.R. Bilateral
frontotemporal
N.R. methohexital,
glycopyrrolate,
succinylocholin
N.R. 58
Moreno,
1998
Case
report
1 No First Bilateral 2.5s duration at
an intensity of
0.7A
0.01 mg/kg
atropine,
thiopental and
succinylcholine
17s-rst seizure,24s,
22s/total duration 186s
9
Ozgul et al.
(2014)
Case
report
1 N.R. First Bilateral
frontotem
poral
N.R. H2antagonist+1
mL/kg Propofol
+1 ml =L/kg
succinylcholine
(muscle relexant)
mean =20s (EMG),25s
(EEG)
10
Pesiridou
et al.
(2010)
Case
report
1 Yes Third Unilateral
(right)- >
bilateral-
bifrontal
2.5-s stimulus
duration, and
800-mA
Metholexial (170
mg) after
decreased,
etomidate, and
succinylocholine
(100 mg)
35.5s (EEG) 6
1 N.R. Bifrontal N.R. N.R. N.R. 7
(continued on next page)
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
450
Table 3 (continued )
Study Study
design
#participants Concomitant
treatment
Trimester
at start of
stimulation
Electrode
placement:
Stimulus
parameters
Anesthetic used Seizure duration #sessions
Pinette et al.
(2007)
Case
report
Second and
third
Rineh et al.
(2020)
Case
report
1 No Third N.R. N.R. Ranitidine,
metoclopramide,
propofol 120 mg
and
succinylcholine
60 mg
N.R. 6
Salzbrenner
et al.,
2011
Case
report
1 N.R. Third Bilateral
Temporal
Dose titration
schedule,
stimulus
intensity was
increased
progressively to
75% of
maximum on
subsequent
sessions
Glycopyrrolate,
ondasetron,
bicitrate, esmolol,
labetalol- >
remifentanil,
methohexital
100150 mg and
succinylcholine
100120 mg
N.R. 9
Sherer
(1991)
Case
report
1 Yes Third Bilateral
Temporal
30% energy
(pulsed
bidirectional
square-wave
stimulus with a
xed pulse
width of I msec
and a frequency
of 70 Hz)
thiopental sodium
125 mg, and
succinylcholine
50 mg
50 s (rst session) 7
Watanabe
et al.
(2019)
Case
report
1 Yes Third Bilateral -brief
pulse
electrical
stimulus of
10%25%
N.R. N.R. 6
Wise et al.
(1984)
Case
report
1 N.R. Second UL non-
dominant
hemisphere
N.I. general
anesthesia, the
pharmacological
agent not
mentioned
N.R. 12
ECT- postpartum
Forray &
Ostroff
(2007)
Case
report
5 Yes First 12
months
postpartum
Bilateral Mean energy
(J):17.5
ketamine Mean EEG seizure
duration:97.1
10
Yes Bilateral 16.1 Propofol replaced
to ketamine
57.5 18
Yes Bilateral 41.5 Propofol replaced
to ketamine
29.8 12
Yes Bilateral 18.9 Thiopental
replaced to
propofol and then
to ketamine
60.8 18
Yes Bilateral 32.1 Methohexital 74.5 6
Gressier
et al.
(2015)
Case
report
1 Yes N.R. N.R. N.R. N.R. N.R. 28
Kisa et al.
(2005)
Case
report
1 No Two moths
postpartum
Bifrontal dynamic energy
23.6 J, pulse
width 1.0 ms,
frequency 90
Hz, duration
1.2 s, current
800 mA)
40 mg propofol
and 40 mg
succinylcholine
1st-30s, 2-150s-interrup-
ted with 3 mg midazolam
i.v. (on ciprooxacine),
3rd - after ciprooxacins
discontinuation - 70s,
4th - 35s, after no seizure
longer than 70s
8
Robinson
and
Stewart
(1986)
Case
report
1 Yes Six weeks
postpartum
N.R. N.R. N.R. N.R. 8
Levy et al.
(2012)
Case
report
3 Yes N.R. Unilateral
(right)ultra-
brief pulse-
pulse width
0.3 ms;
Total dose (mc)
=2833
Propofol
Remifentanil
Suxamethonium
20 10
Yes N.R. 3594 Propofol
Suxamethonium
34 20
Yes N.R. 1129 Propofol
Suxamethonium
33 9
Strain et al.
(2012)
Case
report
1 Yes 5 months N.R. N.R. N.R. N.R. 6
Takubo
et al.
(2019)
Case
report
1 Yes N.R. N.R. N.R. N.R. N.R. N.R.
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
451
pain (Bozkurt et al., 2007), contractions (Pesiridou et al., 2010; Rineh,
2020; Watanabe et al., 2019), increased blood pressure and increased
heart rate (DeBattista et al., 2003; Livingston et al., 1994; Salzbrenner
et al., 2011; Wise et al., 1984). Additionally, prolonged seizures were
reported in one patient on ciprooxacin (Kisa et al., 2005) and memory
loss was mentioned in two other reports (Livingston et al., 1994;
Pesiridou et al., 2010).
As for neonatal safety of ECT, pregnancy complications were re-
ported by several studies, such as vaginal bleeding and a miscarriage
(Moreno et al., 1998), threatened premature labor (Ceccaldi et al., 2008;
Pesiridou et al., 2010), preterm labor (Kasar et al., 2007; Livingston
et al., 1994), abruptio placentae in association with transient hyper-
tension (Sherer, 1991), vaginal bleeding (Livingston et al., 1994), and
miscarriage post ECT session (Livingston et al., 1994). Also, four studies
reported the newborn Apgar below seven at the rst minute (Pinette
et al., 2007; Livingston et al., 1994; Sherer, 1991), and three reported
the Apgar below seven at the fth minute (Livingston et al., 1994;
Pinette et al., 2007). These scores are considered to be eventually un-
related to ECT. Tonic extension posturing of upper extremities with
small left cerebellar, bihemispheric deep white matter, and cortical in-
farcts were detected by tomography and magnetic resonance image
were reported by Pinette et al. (2007) but the relation to ECT is purely
speculative. Moreover, in utero complications such as fetal tachycardia
induced by maternal hypoxia, uterine contractions (Bhatia et al., 1999;
Watanabe et al., 2019), and transient deceleration of fetal heart rate
(Bhatia et al., 1999; Bozkurt et al., 2007; DeBattista et al., 2003; De Asis
et al., 2013; Livingston et al., 1994; Rineh et al., 2020) were as well
reported. In De Asis et al. (2013), fetal heart rate decelerations were
attributed to methohexital for anesthesia and in Sherer et al. (1991) a
reduced fetal heart rate variability was attributed to intravenous thio-
pental sodium. Interestingly, for ECT in the postpartum, only one study
reported transient memory loss (Forray and Ostroff; 2007), whereas the
remaining six did not mention ECT adverse effects.
3.2.4. Acceptability
Acceptability was calculated from the number of dropouts. The RCT
in rTMS during pregnancy showed that 84.6% women completed the
intervention (Kim et al., 2018). In the single-arm studies, all but one
participant completed the treatment (93.75%) and across case reports
all women completed treatment (100%).
As for the rTMS studies conducted in the postpartum period, all
women recruited for the RCT (Myczkowski et al., 2012) and for the
single-arm study (Cox et al., 2020) completed the treatment protocol. In
Brock et al. (2016), 76% completed the treatment, and in Garcia et al.
(2010), 89% completed the treatment with a mean acceptability rate
across single-arm studies of 88,3%. Finally, in the case report by Odgen
et al. (1999) the patient completed the treatment.
Considering TES in pregnancy, the RCT by Vigod et al. (2019) lost
four participants (two from the active group and two from the sham
group), two of which withdrew prior to starting, meaning an estimated
dropout rate of 80%. From the participants anticipated for the
single-arm study by Palm et al. (2017), results reported three completers
and it is not clear if the remaining seven were not enrolled or lost. The
patients described in TES case studies in pregnancy completed the
treatments. No studies have been published in the postpartum.
Studies of ECT in PPD are limited to case reports, describing 36 case
studies. Although the assessment of treatment acceptability according to
dropout rates is biased by nature, treatment stoppage or discontinuation
was reported in pregnant women, due to the incidence of adverse effects
such as contractions and risk of preterm labor (Ceccaldi et al., 2008;
Watanabe et al., 2019; Kasar et al., 2007), the observation of cognitive
decline (Salzbrenner et al., 2011), transportation difculties (Bozkurt
et al., 2007) or other unknown reasons (Maletzky et al., 2004). Summing
an estimated ECT acceptability in pregnancy of 83.2%. In the post-
partum, all patients described completed the treatment suggesting an
acceptability of 100% (see Table 6).
3.2.5. Neurocognitive assessment
Only a few studies reported neurocognitive outcomes across treat-
ment. Regarding rTMS during pregnancy, the RCT by Kim et al. (2018)
collected data using the Mini-Mental State Examination (MMSE), the
Trail Making Test A&B (TMT-A; TMT-B), the Stroop Interference Test,
the Wechsler Memory Scale 3rd Edition, the Letter-Number Sequencing
(LNS), and the Wechsler Memory Scale 3rd Edition and Digit Span. The
authors found signicant differences in LNS with the active group per-
forming worse in post-treatment when compared to pre-treatment. No
other results were made available.
In the postpartum period, Myczkowski and colleagues(2012), used
a neuropsychological battery that included the MMSE, the TMT-B, and
the Stroop Test-Interference. A statistically signicant difference was
found between the active and the sham groups in the TMT-B (31.4%
versus 12.9%; p =.039) and in the Stroop Test-Interference (31.7%
versus 10.0%; p =.034) with the active group outperforming. However,
these differences did not survive false discovery rate for multiple com-
parisons. Similarly, in the postpartum period, Cox et al. (2020) did not
nd statistically signicant differences between baseline scores and end
of treatment in the MMSE, the TMT-B, and the List Generation. The tDCS
study by Palm et al. (2017), measured the scores of TMT A&B at base-
line, at week 2 of treatment and at follow-up in three patients with data
suggesting neuropsychological improvement. The case report by Wilk-
ening et al. (2019) using tACS, presented TMT-A&B scores at baseline, at
the end of treatment and at follow-up and both tests showing
improvement. Trevizol et al. (2015) observed the impact of TNS in
cognitive functions using the Montreal Cognitive Assessment (MOCA)
and found stable cognitive performance and improved memory. In ECT,
only Salzbrenner et al. (2011) assessed neurocognitive performance
using the MMSE and suggest nine as the maximum number of sessions
before cognitive decline.
3.2.6. Risk of bias
Two out of the three RCT were assessed with high RoB (see Table S1
in supplementary materials). RoB across NRS studies was considered
critical due to incomplete information and confounding (see Fig. 2 and
Fig. 3, as well as Table S2 in supplementary materials to support the
interpretation of results). For case-series and case-studies, to guarantee
the homogeneous assessment, the criterion of a minimum follow-up
length of 6 months was established, based on our clinical and experi-
mental judgment. Across interventions, RoB was found to be high as the
majority did not establish the outcome measures a priori, did not blind
the assessment of outcome measures, and did not complete the follow-up
length of 6 months. The case studies using rTMS and TES during preg-
nancy, scored the highest (meaning the lowest RoB). These were fol-
lowed by rTMS studies in the postpartum mainly threatened by the lack
of a priori establishment of outcome measures, or these were not
appropriate, or because the authors did not apply procedures for
blinding assessments. The most threatened reports were the ECTs con-
ducted through the peripartum period with a generalized absence of
critical information across all parameters (see Table S3 in supplemen-
tary materials).
4. Discussion
This study aimed to gather the available literature on the efcacy of
NIBS techniques in PPD, combining and updating previous reviews (Kim
et al., 2015; Konstantinou et al., 2020). We collected data from 54 re-
ports, gathering the information about 173 women under treatment.
Note. *Applied stimulation during pregnancy and throughout the postpartum period. ECT =electroconvulsive therapy; N.R. =not reported; N.A. =Non applicable;
EEG =electroencephalogram.
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
452
Table 4
Reports of efcacy for the included studies.
Study #
participants
Primary Psychiatric Diagnosis Endpoint Baseline
(mean)
Final (mean) Remission (#
participants)
Response (#
participants)
rTMS-pregnancy
Burton et al., 2014* 1 PPD (pregnancy) HDRS-
21
4 Successful maintenance treatment
Cohen et al. (2008) 1 BDII during pregnancy HDRS-
17
18 6 1 1
Ferr˜
ao & Silva (2018) 3 PPD (pregnancy) HDRS-
21
24.3 7.3 2 3
1 PPD (pregnancy) HDRS-
22
12 6 1 1
Gahr et al. (2012) 1 PPD (pregnancy) N.R. N.R. N.R. N.R. N.R.
Klirova et al. (2008) 1 PPD (pregnancy) MADRS 33 2 1 1
1 PPD (pregnancy) BDI 29 12 0 1
Kim et al. (2018) 11 active PPD (pregnancy) HDRS-
17
23.2 9.3 3 9
11 sham PPD (pregnancy) HDRS-
17
22.3 13.2 2 5
Kim et al. (2011) 10 PPD (pregnancy) HDRS-
17
24.4 9.7 3 7
Nahas et al. (1999) 1 PPD (pregnancy) HDRS 32 15 0 1
¨
Ozten et al. (2013) 1 PPD (pregnancy) HDRS-
17
29 8 0 1
Sayar et al. (2014) 30 PPD (pregnancy) HDRS-
17
26.8 13 6 12
Tan et al., 2008* 1 PPD (pregnancy) HDRS-
17
38 4 1 1
Tarhan et al. (2012) 7 PPD (pregnancy) HDRS-
17
N.R. N.R. 2 5
Trevizol et al. (2019)
**
1 PPD (pregnancy) QIDS-SR 10 3 1 1
Xiong et al. (2018) 1 BDII during pregnancy EPDS 23 4 1 1
Zhang et al. (2010) 1 PPD (pregnancy) HDRS-
24
35 8 0 1
Zhang and Hu (2009) 3 PPD (pregnancy) HDRS-
17
N.R. N.R. N.R. N.R.
rTMS-pospartum
Brock et al. (2016) 19 PPD (postpartum) EPDS 20.6 8.2 14 N.I.
Cox et al. (2020) 6 PPD (postpartum) EPDS 16.33 9.33 4 2
Garcia et al. (2010) 9 PPD (postpartum) HDRS-
24
23.4 2.1 8 N.R.
Myczkowski (2012) 8 active PPD (postpartum) HDRS-
17
29.1 18.38 N.R. N.R.
6 sham PPD (postpartum) HDRS-
17
26.7 21.8 N.R. N.R.
Odgen et al. (1999) 1 PPD (postpartum) HDRS-
17
29 3 1 1
TES-pregnancy
Palm et al., 2017*** 3 PPD (pregnancy) HDRS-
21
24.7 7.0 1 N.R.
Sreeraj et al., 2016*** 1 PPD (pregnancy) HDRS-
17
18 6 (at 1-month
FU)
1 1
Trevizol et al.,
2015*****
1 PPD (pregnancy) HDRS-
17
26 5 1 1
Vigod et al., 2019*** 10 active PPD (pregnancy) MADRS 23.5 11.8 6 N.I.
10 sham PPD (pregnancy) MADRS 26.8 15.4 2 N.I.
Wilkening et al.,
2019****
1 PPD (pregnancy) HDRS-
21
19 11 0 1
+
ECT pregnancy
Bhatia et al. (1999) 2 PPD (pregnancy) N.R. N.R. N.R. N.R. N.R.
Bozkurt et al. (2007) 1 Psychotic depression HDRS 33 3 1 1
Brown et al. (2003) 1 Psychotic depression N.R. N.R. N.R. N.R. N.R.
Ceccaldi et al. (2008) 1 PPD (pregnancy) HDRS N.R. N.R. N.R. N.R.
De Asis et al. (2013) 1 PPD (pregnancy) N.R. N.R. N.R. 1 N.R.
DeBattista et al. (2003) 1 PPD (pregnancy) HDRS 31 7 1 1
Erturk et al. (2020) 1 MD (pregnancy) N.R. N.R. N.R. N.R. N.R.
Gahr et al. (2013) 1 PPD (pregnancy) BDI 56 4 1 1
Gonzales et al. (2014) PPD with psychotic features
(pregnancy) and catatonia
N.R. N.R. N.R. N.R. N.R.
Kasar et al. (2007) 1 PPD with psychotic features
(pregnancy)
HDRS 47 15 1 1
Livingston et al.,
1994*
1 Severe PPD (pregnancy) N.R. N.R. N.R. N.R. N.R.
Maletzky (2004) 4 PPD (pregnancy) CGI N.R. 3.9 N.R. N.R.
N.R. 3.2 N.R. N.R.
(continued on next page)
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
453
Overall, NIBS are promising for treating PPD, being effective, potentially
safe, and beneting from signicant acceptability by women. Particular
attention to the specicities of each intervention will be discussed in the
following paragraphs.
rTMS seems to be efcacious in PPD both during pregnancy and the
postpartum period. Bilateral, left-HF, right-LF and left-LF protocols were
so far tested. Studies in the postpartum period followed the principles of
rTMS use in MDD, with the left-HF in the DLPFC being the single pro-
tocol under study. Overall, a decrease in depressive symptoms occurred
between baseline and the end of treatment, except for Gahr et al. (2013)
which described a woman who experienced no benet with rTMS as an
add-on treatment to ECT. In pregnancy, left-HF was the most common
protocol across reports, followed by right-LF, with both alternatives
showing encouraging results. No comparative reports establishing the
advantage of one protocol over the other are available. Despite the
literature suggesting that the severity of PPD decreases over time,
potentially resolving within three to 12 months after delivery (Stein
et al., 1991; Torres et al., 2019), PPD frequently becomes chronic
(Vliegen et al., 2014), suggesting high heterogeneity among peripartum
women.
The most common neonatal event after rTMS was preterm birth,
highlighting its potential association with the treatment. Hence, Kim
et al. (2018) reports of three preterm births need to be further examined.
However, unlike what is reported as potentially associated with expo-
sure in utero to antidepressants and ECT, none of the included rTMS
studies described cardiac malformation, persistent pulmonary hyper-
tension, or other in utero complications. The most frequent adverse ef-
fect for mothers was a transient benevolent headache when compared to
the common antidepressants side effects such as nausea and diar-
rhea/loose stool, or the potential cognitive decline in ECT. Together,
these data suggest that regarding the risk-benet ratio, rTMS research is
worth pursuing.
Of note, although breastfeeding was not dened as a study outcome,
we found that during the postpartum period, most mothers were
breastfeeding. As this may be a factor of treatment acceptability in
postpartum women, rTMS may resonate with those reluctant to use
medication in the perinatal period that seek alternative medication-free
treatments (Hamdan and Tamim, 2012; Walton et al., 2014). In fact,
rTMS was overall acceptable, with only 8,04% of women discontinuing
treatment.
The benets or drawbacks of rTMS in neurocognitive performance in
the peripartum have been barely reported and the limited data available
is controversial. The modest evidence for a specic impact of rTMS in
cognition in the peripartum period is in line with similar reports for
MDD, generally (Martin et al., 2017). Furthermore, considering that
brain plasticity in the peripartum interferes with cognitive performance
(Bannbers et al., 2013; Glynn, 2010) acting as a confounder, no partic-
ular assumption is currently possible.
In sum, the available data suggests caution regarding rTMS as a
legitimate option for women diagnosed with PPD, both concerning its
Table 4 (continued )
Study #
participants
Primary Psychiatric Diagnosis Endpoint Baseline
(mean)
Final (mean) Remission (#
participants)
Response (#
participants)
PPD with psychotic features
(pregnancy)
PPD (pregnancy) N.R. 3.5 N.R. N.R.
PPD with psychotic features
(pregnancy)
N.R. 4.0 N.R. N.R.
Moreno et al. (1998) 1 Severe PPD with psychotic symptoms
(pregnancy)
N.R. N.R. N.R. 1 N.R.
Ozgul et al. (2014) 1 PPD (pregnancy) N.R. N.R. N.R. N.R. N.R.
Pesiridou et al. (2010) 1 Depressive symptoms during
pregnancy
BDI 33 15 0 1
Pinette et al. (2007) 1 PPD (pregnancy) N.R. N.R. N.R. N.R. N.R.
Rineh et al. (2020) 1 PPD (pregnancy) N.R. N.R. N.R. 1 N.R.
Salzbrenner et al.
(2011)
1 Bipolar depression (pregnancy) MADRS 32 12 0 1
Sherer (1991) 1 PDD with psychotic features
(pregnancy)
N.R. N.R. N.R. N.R. N.R.
Watanabe et al. (2019) 1 PPD (pregnancy) HDRS-
24
36 26 0 0
Wise et al., 1984 1 Psychotic PPD (pregnancy) N.R. N.R. N.R. N.R. N.R.
ECT postpartum
Forray & Ostroff
(2007)
5 Mood disorder not otherwise specied N.R. N.R. N.R. Women were treated until remission was
achieved Postpartum psychosis, bipolar I
MDD, psychotic features
Bipolar I, mixed episode
MDD, psychotic features
Gressier et al. (2015) 1 PPD (postpartum) HDRS-
17
32 3 1 1
Kisa et al. (2005) 1 PPD (postpartum) N.R. N.R. N.R. N.R. N.R.
Levy et al. (2012) 3 PPD (postpartum) EPDS 22 2 1 1
EPDS 21 4 1 1
N.I. N.I. N.I. N.I. N.I.
Robinson and Stewart
(1986)
1 PPD (postpartum) with psychotic
symptoms
N.R. N.R. N.R. N.R. N.R.
Strain et al. (2012) 1 Postpartum depression with
Psychomotor retardation
Postpartum psychosis
N.R. N.R. N.R. 1 1
Takubo et al. (2019) 1 PPD (postpartum) HDRS 35 7 1 1
Note. *Applied stimulation during pregnancy and throughout the postpartum period. **Used iTBS; iTBS =intermittent theta burst. ***Used tDCS. tDCS =transcranial
direct current stimulation. ****Used tACS. tACS =transcranial alternating current stimulation. *****Used TNS; TNS =trigeminal nerve stimulation. rTMS =repetitive
transcranial magnetic stimulation. TES =transcranial electric etimulation. MDD =Major Depressive Disorder. BD=Bipolar Depression. HDRS=Hamilton Depression
Rating Scale. MADRS =Montgomery-Asberg Depression Rating Scale. EPDS =Edinburgh Postnatal Depression Scale. QIDS-SR =Quick Inventory of Depressive
Symptomatology Self-Report. DASS: Depression Anxiety Stress Scales. D =depression. A =Anxiety. TES =tDCS =transcranial Direct Current Stimulation. ECT =
electroconvulsive therapy. N.R. =not reported; N.A. =Not applicable.
+
Response at 30% from baseline.
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
454
Table 5
Safety of the included studies.
Study Adverse effects (mothers) Neonatal safety
rTMS pregnancy
Burton et al.,
2014*
N.O. N.O.
Cohen et al.
(2008)
N.R. N.R.
Ferr˜
ao & Silva
(2018)
Pain/discomfort at application
site, transient difculty in
concentration, sore throat
1 pre-term birth, 1 baby
APGAR score =6
Gahr et al.
(2012)
N.R. N.R.
Kim et al.
(2018)
Headache, dizziness, nausea,
Pain/discomfort at application
site, supine hypotension, jaw
pain and eye twitch
3 pre-term births
Kim et al.
(2011)
Mild headache, supine
hypotension
N.R.
Klirova et al.
(2008)
N.A. 1 pre-term birth
Nahas et al.
(1999)
Tension in the abdominal
muscles at the pelvic line
(probably due to anxiety)
N.R.
¨
Ozten et al.,
2013
N.R. N.O.
Sayar et al.
(2014)
Contraction of facial muscles N.R.
Tan et al.,
2008*
N.R. 1 pre-term birth
Tarhan et al.
(2012)
N.O. N.R.
Trevizol et al.
(2019) **
N.R. N.O.
Xiong et al.
(2018)
N.R. N.O.
Zhang et al.
(2010)
N.O. N.O.
Zhang and Hu
(2009)
N.R. N.O.
rTMS postpartum
Brock et al.
(2016)
N.O. N.A.
Cox et al.
(2020)
Headache and scalp
discomfort
N.A.
Garcia et al.
(2010)
Headache, pain at application
site and facial stimulation
N.A.
Myczkowski
et al. (2012)
Minor scalp discomfort and/or
mild headache
N.A.
Odgen et al.
(1999)
N.R. N.A.
TES pregnancy
Palm et al.
(2017)
N.O. N.R.
Sreeraj et al.
(2016)
Transient, mild burning
sensations at application site
and eeting experience of
phosphenes
N.R.
Trevizol et al.
(2015)
N.R. N.O.
Vigod et al.
(2019)
buzzingor tingling
application site
1 pre-term birth
Wilkening et al.,
2019*
Mild phosphenes during
stimulation
N.R.
ECT-pregnancy
Bhatia et al.
(1999)
Case 1: Uterine contractions
Case 2: N.O.
Case 1: Cardiac decelerations
Case 2: preterm labor
+
Bozkurt et al.
(2007)
Pelvic pain after the 8th and
9th ECT
Fetal decelerations after 13th
and 16th ECT
Brown, 2003 N.R. N.R.
Ceccaldi et al.
(2008)
N.R. preterm birth
De Asis et al.
(2013)
N.R. Fetal decelerations caused by
anesthetic use
DeBattista et al.
(2003)
Maternal HR and blood
pressure increase
Decelerations during the
seizure and immediately post
ictally
Table 5 (continued )
Study Adverse effects (mothers) Neonatal safety
Erturk et al.
(2020)
N.O. N.O.
Gahr et al.
(2013)
N.O. N.O.
Gonzales et al.
(2014)
N.O. N.O.
Kasar et al.
(2007)
N.R. After 4th ECT session-
contractions - preterm labor
cesarean section
Livingston
et al., 1994*
blood pressure and pulse rate
were slightly higher after ECT
than pretreatment
Fetal HR deceleration during
third ECT
Preterm birth: Twins with
congenital malformations
the patient received
chemotherapy even during
early pregnancy -A: Apgar 6
(1) and 7 (5) Twin-B: Apgar
6 (1) and 8 (5)
Maletzky
(2004)
N.R. N.R.
Moreno et al.
(1998)
Vaginal bleeding after 2nd
session. Miscarried post 3rd
ECT session
N.O.
Ozgul et al.
(2014)
N.R. N.O.
Pesiridou et al.
(2010)
At the 3rd session
-disorientation, confusion,
short-term memory
difculties, painful
contractions
N.O.
Pinette et al.
(2007)
labor induction at 36.1 weeks
of gestation
+
APGAR - 1 min - 4, 5 min7,
small left cerebellar,
bihemispheric deep white
matter and cortical infarcts
upper extremities were tonic
with extension posturing
expected long term motor
control issues
Rineh (2020) intermittent contraction Transient episode of fetal
heart rate reduction was
observed at the second session
Salzbrenner
et al., 2011
cesarean delivery at 38 +6
because of preeclampsia and
breech presentation because of
preeclampsia and breech
presentation
+
N.R.
Sherer (1991) abruptio placentae in
association with transient
hypertension
Apgar 3 (1)
Watanabe et al.
(2019)
Uterine contractions, retarded
oxygenation during the
procedure resulting in
maternal hypoxia
fetal tachycardia, threatened
preterm labor
Wise (1984) N.O. N.O.
ECT-postpartum
Forray & Ostroff
(2007)
transient memory loss during
the initial ECT treatments
N.A.
Gressier, 2015 N.R. N.A.
Kisa et al.
(2005)
Prolonged seizures due to co-
administered medication
N.A.
Levy (2012) N.O. N.A.
Robinson and
Stewart
(1986)
N.R. N.A.
Strain et al.
(2012)
N.R. N.A.
Takubo et al.
(2019)
N.R. N.R.
Note. *Applied stimulation during pregnancy and throughout the postpartum
period. **Used iTBS. iTBS =intermittent theta burst stimulation. ***Used tDCS.
tDCS =transcranial direct current stimulation. ****Used tACS. tACS =trans-
cranial alternating current stimulation. *****Used TNS; TNS =trigeminal nerve
stimulation. rTMS =repetitive transcranial magnetic stimulation. TES =trans-
cranial electric stimulation. ECT =electroconvulsive therapy. N.R. =Not
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
455
efcacy and safety. Although the single RCT conducted during preg-
nancy showed the highest benet, further research is needed to explore
the possible association between rTMS and premature birth. In future
research, this link needs to be addressed in the context of the well-known
relationship between prenatal depression and preterm birth (Jarde et al.,
2016) and the impact of each variable needs to be disentangled. Com-
plementary vectors of research aimed at ne-tunning treatment pa-
rameters are also welcome for head-to-head studies comparing left-HF
and right-LF montages, as the latter is experienced with much less
discomfort by mothers. Despite some resistance about the use of rTMS in
pregnancy, its use in the postpartum period seems to be particularly
benecial with no adverse effects to the newborn expected through
breastfeeding and only minor and transient side effects to mothers.
Additionally, because studies observing the antidepressant effect of
rTMS in the peripartum used concomitant medication, future research
must control for this confounder. Lastly, to ascertain rTMS position in
the pathway of perinatal mental health care, large sample controlled
clinical trials should be prioritized.
All TES reports included were conducted in pregnancy and showed
clinical benets across techniques. Despite the limited evidence about its
antidepressant efcacy, TES is certainly a eld worth pursuing. In
particular, the F3F4 tDCS montage within a protocol of 15 daily ses-
sions, as dened by Vigods RCT (2019), seems to be the best research
approach, the safest clinical option available beneting of good
acceptability. Also, the potential association between TES and preterm
birth (Vigod et al., 2019) highlights the need for more investigation. The
impact of TES in neurocognitive measures in the peripartum is still
barely explored but so far showed to be benecial. Because the available
TES studies were conducted during pregnancy, information regarding
the willingness to maintain breastfeeding while in treatment is not
available. The use of concomitant medication was not allowed in TES
studies, clearing medication as a potential confounder of its efcacy.
However, despite its promising features, the limited number of studies,
the small sample sizes, and the high risk of bias compromise strong
positioning regarding TES and future controlled studies with larger
samples are needed.
Although the present study showed good rates of acceptability both
for rTMS and TES, more can be done regarding acceptability. In fact, the
peripartum period is very challenging, highlighting the need to have
alternatives that are not only effective but also that overcome
demanding clinic-based NIBS treatments. Home-based versions of NIBS
treatments are very attractive as they optimize individual resources
while enabling patients to actively contribute to managing their mental
health. In particular, home-based tDCS has been tested successfully in
several neuropsychiatric disorders including depression (e.g. Alonzo
et al., 2019) and may well be the next step in PPD, freeing patients from
the clinic-setting. However, to guarantee tDCS safe and effective appli-
cation, three conditions must be satised: 1) The tDCS device has to
include electronic remote supervision (such as single session code-locks
and other dose control mechanisms) and has to collect post-stimulation
information to assess compliance and quality of stimulation (e.g. time of
start and completion, interruption and restart of the session), sending
alert signals to health care professionals; 2) the tDCS treatment should
be accompanied by the appropriate assessment and training provided to
patients regarding the minimum skills required to comply with the
treatment; 3) tDCS should be complemented by eHealth solutions, for
supervision and collection of real-time data to improve adherence and
inform clinical decision.
Although our review is suggestive of the clinical benets of ECT in
severely depressed women, currently available data is restricted to case
studies and case-series with high RoB. When balancing the risk-benets
ratio of ECT in PPD, safety issues must be carefully weighted particularly
for pregnant women and for the fetus. Seizures and the impact of
reported. N.A. =Not applicable. N.O. =Not observed
+
apparently unrelated to
ECT.
Table 6
Acceptability for the included studies.
Study Number of participants
Recruited Completed
rTMS-pregnancy
Burton et al., 2014* 1 1
Cohen et al. (2008) 1 1
Ferr˜
ao & Silva (2018) 4 4
Gahr et al. (2012) 1 1
Kim et al. (2018) 14 active 11 active
12 sham 11 sham
Kim et al. (2011) 10 10
Klirova et al. (2008) 2 2
Nahas et al. (1999) 1 1
¨
Ozten et al., 2013 1 1
Sayar et al. (2014) 30 29
Tan et al., 2008* 1 1
Tarhan et al. (2012) 7 7
Trevizol et al. (2019) ** 1 1
Xiong et al. (2018) 1 1
Zhang et al. (2010) 1 1
Zhang and Hu (2009) 3 3
rTMS postpartum
Brock et al. (2016) 25 19
Cox et al. (2020) 6 6
Garcia et al. (2010) 9 8
Myczkowski et al. (2012) 14 14
Odgen et al. (1999) 1 1
TES pregnancy
Palm et al. (2017) 3 3
Sreeraj et al. (2016) 1 1
Trevizol et al. (2015) 1 1
Vigod et al. (2019) 10 active 8 active
10 sham 8 sham
Wilkening et al., 2019* 1 1
ECT-pregnancy
Bhatia et al. (1999) 2 2
Bozkurt et al. (2007) 1 1
Brown et al. (2003) 1 1
Ceccaldi (2008) 1 1
De Asis et al. (2013) 1 1
DeBattista (2003) 1 1
Erturk et al. (2020) 1 1
Gahr et al. (2013) 1 1
Gonzales 2014 1 1
Kasar et al. (2007) 1 1
Livingston et al. (1994) 1 1
Maletzky (2004) 4 4
Moreno et al. (1998) 1 1
Ozgul et al. (2014) 1 1
Pesiridou et al. (2010) 1 1
Pinette et al. (2007) 1 1
Rineh (2020) 1 1
Salzbrenner et al. (2011) 1 1
Sherer et al. (1991) 1 1
Watanabe et al. (2019) 1 1
Wise (1984) 1 1
ECT-postpartum
Forray & Ostroff (2007) 5 5
Gressier et al. (2015) 1 1
Kisa et al. (2005) 1 1
Levy et al. (2012) 1 1
Robinson and Stewart, 1986 1 1
Strain et al. (2012) 1 1
Takubo et al. (2019) 1 1
Note. *Applied stimulation during pregnancy and throughout the postpartum
period. **Used iTBS. iTBS =intermittent theta burst stimulation. ***Used tDCS.
tDCS =transcranial direct current stimulation. ****Used tACS. tACS =trans-
cranial alternating current stimulation. rTMS =repetitive Transcranial Magnetic
Stimulation. TES =transcranial electric stimulation. ECT =electroconvulsive
therapy. N.I. =No information. N.A. =Not applicable.
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
456
Fig. 2. Trafc light plot for Risk of Bias of individual studies.
Fig. 3. Weighted summary plot for Risk of Bias of individual studies.
F. Pacheco et al.
Journal of Psychiatric Research 140 (2021) 443–460
457
concurrent medication and anesthesia seem to be associated to preg-
nancy and/or delivery complications and to severe in utero complica-
tions. Whilst only anecdotal evidence is available on the impact of ECT
in neurocognitive performance of peripartum women, the information
available suggests a potential cognitive decline associated with ECT,
leading to similar concerns as those described in the literature for MDD.
Breastfeeding is frequently compromised in ECT, as acute treatments are
completed during in-patient regimen where infants are not allowed to
stay, and mother-infants units are still an infrequent reality. However,
despite the decisional conict concerning the compatibility of the
anesthetic drugs used during ECT with breastfeeding, there is some
evidence showing no adverse effects of these drugs to breastfed infants
(Babu et al., 2013). Our review observed this practice with most studies
reporting that patients were not breastfeeding during treatment and
only one reporting that the patient did not stop breastfeeding. Of note,
the available data in ECT is limited to the course of the acute treatment,
with only scarce information about treatment maintenance and
follow-up.
5. Conclusions
Although our review advances the eld by exploring the efcacy of
NIBS in reducing PPD, it has also some limitations. Firstly, the available
reports regard studies with small sample sizes, mainly single-arm or case
report studies, with moderate to high/critical RoB. To better understand
the current situation, we did not exclude low-quality reports, but this
warrants cautious conclusions. The quality of the data extracted from
ECT reports is fragile as it fully relies on case reports. Further, the design
of the studies hampers conclusions regarding comparative treatments (e.
g., treatment vs active comparators or placebo). Thus, any analysis
aiming at understanding the impact of NIBS in PPD is currently limited
to the comparison between baseline and the end of treatment. Also, is-
sues of clinical signicance can be raised as we estimated differences
between baseline and end of treatment scores that are expected to
spontaneously decrease along the course of the disease. Although we
aimed for meta-analyses, these limitations would raise issues on its
robustness.
In the eld of NIBS, rTMS is the technique that benets from the most
robust research, with promising results regarding efcacy but some
pending questions when it comes to safety during pregnancy. In the
postpartum period, the positive perspective towards NIBS efcacy sug-
gests that whenever available, women diagnosed with mild to moderate
PPD, and particularly those who do not wish to start medication, should
be offered rTMS/TES as an alternative treatment. However, in preg-
nancy caution is needed until new ndings allow for the clarication
about the contribution of these treatments to preterm birth. Although
the overall efcacy and safety prole of TES was found to be good across
reports, only anecdotal RCTs and single-arm studies were available,
limiting this treatment as a current clinical option. As for ECT, until
further investigation, the nature and low quality of the available data
suggest it should be considered only for severe cases and when no other
alternative is available. Furthermore, in every clinical situation for
which ECT is suggested, the risk-benet balance must be assessed, and
the patient and the fetus need to be closely monitored for the impact of
the seizures and the anesthesia (with particular attention to fetal heart
rate variability during the rst trimester, and to obstetric
complications).
Of interest, although NIBS seems to be acceptable to women, no data
is available regarding its acceptability by health practitioners, who have
a core role in the process of referring and implementing novel health
interventions. This vector of research should be explored aiming for the
uptake of safe and efcacious treatments by the perinatal mental health
systems. Hence, NIBS seems to constitute an alternative to medication
and psychotherapy and can be added into combined treatments as well.
Larger RCTs are needed for comparative studies strengthening the eld
and clarifying the position of each technique within the algorithms of
perinatal mental health care.
Funding
Ana Os´
orio received nancial support from CAPES/Proex (grant no.
0653/2018). Ana Os´
orio and Ana Ganho-´
Avila received support from
CAPES/PrInt (grant no. 88887.310343/2018-00).
Declaration of competing interest
Ana Ganho-´
Avila and Andr´
e Brunoni report to have had non-
financial support from Soterix and commercial interests with Flow
Neuroscience tDCS equipment, during the course of the study. The
remaining authors declare no conicts of interest.
Acknowledgement
This article/publication is based upon work from COST Action 18138
- Research Innovation and Sustainable Pan-European Network in Peri-
partum Depression Disorder (Riseup-PPD), supported by COST (Euro-
pean Cooperation in Science and Technology). www.cost.eu.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jpsychires.2021.06.005.
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F. Pacheco et al.
... The aims of our review were to identify available studies about tES during pregnancy and the postpartum period in order to investigate its efficacy and safety during the perinatal period. To our knowledge, several reviews have addressed this topic [56][57][58], but the present research has the advantage of including a larger number of studies independently of diagnosis and type of tES used. Thus, we highlighted the complete absence of available data on the use of tES in postpartum disorders and during breastfeeding, including postpartum depression. ...
... In addition, several authors point out that transcutaneous electrical nerve stimulation (TENS), with a strength of 100 mA, has been used safely in pregnancy for decades as pain relief during labor [49,68]. Compared to tES techniques, repetitive transcranial magnetic stimulation (rTMS) has been more widely studied in the perinatal period [57,58,[69][70][71]. Kurzeck et al. [56] emphasized that follow-up examinations of children exposed to rTMS during pregnancy revealed no delay in cognitive or motor development [26]. ...