Psychological Medicine
cambridge.org/psm
Review Article
Cite this article: Shay M, MacKinnon AL,
Metcalfe A, Giesbrecht G, Campbell T,
Nerenberg K, Tough S, Tomfohr-Madsen L
(2020). Depressed mood and anxiety as risk
factors for hypertensive disorders of
pregnancy: a systematic review and meta-
analysis. Psychological Medicine 1–13. https://
doi.org/10.1017/S0033291720003062
Received: 9 January 2020
Revised: 17 July 2020
Accepted: 7 August 2020
Key words:
Hypertensive disorders of pregnancy; maternal
mental health; meta-analysis; perinatal
anxiety; perinatal depression; preeclampsia
Author for correspondence:
Matthew Shay,
E-mail: matthew.shay@ucalgary.ca
© The Author(s) 2020. Published by Cambridge
University Press
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Depressed mood and anxiety as risk factors for
hypertensive disorders of pregnancy: a
systematic review and meta-analysis
Matthew Shay1 , Anna L. MacKinnon2, Amy Metcalfe2,3, Gerald Giesbrecht4,
Tavis Campbell1, Kara Nerenberg2,3,5, Suzanne Tough2,4
and Lianne Tomfohr-Madsen1,4
1
Department of Psychology, University of Calgary, Calgary, Alberta, Canada; 2Community Health Sciences,
Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; 3Department of Obstetrics and
Gynaecology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; 4Department of
Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada and 5Department of
Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
Abstract
Background. Psychosocial factors have been implicated as both a cause and consequence of
hypertension in the general population but are less understood in relation to hypertensive dis-
orders of pregnancy (HDP). The aims of this review were to (1) synthesize the existing litera-
ture examining associations between depression and/or anxiety in pregnancy and HDP and
(2) assess if depression and/or anxiety in early pregnancy was a risk factor for HDP.
Methods. A comprehensive search of Medline, Embase, CINAHL, and PsycINFO was con-
ducted from inception to March 2020 using terms related to ‘pregnancy’, ‘anxiety’, ‘depres-
sion’, and ‘hypertensive disorders’. English-language cohort and case-control studies were
included if they reported: (a) the presence or absence of clinically significant symptoms of
depression/anxiety, or a medical record diagnosis of depression or an anxiety disorder in preg-
nancy; (b) diagnosis of HDP; and/or (c) data comparing the depressed/anxious group to the
non-depressed/anxious group on HDP. Data related to depression/anxiety, HDP, study char-
acteristics, and aspects related to study quality were extracted independently by two reviewers.
Random-effects meta-analyses of estimated pooled relative risks (RRs) were conducted for
depression/anxiety in pregnancy and HDP.
Results. In total, 6291 citations were retrieved, and 44 studies were included across 61.2 mil-
lion pregnancies. Depression and/or anxiety were associated with HDP [RR = 1.39; 95% con-
fidence interval (CI) 1.25–1.54].
Conclusions. When measurement of anxiety or depression preceded diagnosis of hyperten-
sion, the association remained (RR = 1.27; 95% CI 1.07–1.50). Women experiencing depres-
sion or anxiety in pregnancy have an increased prevalence of HDP compared to their non-
depressed or non-anxious counterparts.
Hypertensive disorders of pregnancy (HDP) represent a broad spectrum of disorders ranging
from gestational hypertension and chronic hypertension to non-severe pre-eclampsia (includ-
ing chronic hypertension with superimposed pre-eclampsia) and severe pre-eclampsia (e.g.
eclampsia and HELLP syndrome – hemolysis, elevated liver enzymes, and low platelets)
(Butalia et al., 2018; Magee et al., 2018). Occurring in approximately 10–15% of pregnancies
(Umesawa & Kobashi, 2017), HDP alter in-utero fetal growth conditions and are associated
with elevated risk for preterm birth and increased long-term vascular, psychiatric, and neuro-
developmental outcomes in infants (Maher et al., 2018; Regitz-Zagrosek et al., 2011). HDP are
also associated with adverse short- and long-term maternal outcomes, including increased risk
of maternal morbidity and death, and a higher likelihood of future medical (i.e. stroke, cancer,
and hypertension) and psychiatric (i.e. depression) diagnoses (Filippi, Chou, Ronsmans,
Graham, & Say, 2016; Say et al., 2014).
Depression and anxiety are common during pregnancy, with greater than 10% of women
reporting clinically significant symptoms of depression and more than 30% reporting signifi-
cant anxiety (Leach, Poyser, & Fairweather-Schmidt, 2017; Tebeka, Le Strat, & Dubertret,
2016). Prenatal depression and/or anxiety are risk factors for a number of obstetric complica-
tions and strong predictors of postpartum mental health problems (Alder, Fink, Bitzer, Hösli,
& Holzgreve, 2007; Underwood, Waldie, D’Souza, Peterson, & Morton, 2016). Emerging evi-
dence suggests that the combination of both an HDP and elevated symptoms of depression or
anxiety during pregnancy further increases the risk of adverse obstetrical outcomes including
lower birth weight and lower gestational age at birth (Hilmert et al., 2008; Horsley,
Tomfohr-Madsen, Ditto, & Tough, 2019), with one recent study reporting that reduced ges-
tational age is associated with HDP at all percentiles of self-reported depression or anxiety
 2 Matthew Shay et al.
symptoms (Horsley et al., 2019). Psychosocial factors such as
chronic stress and elevated symptoms of depression and anxiety
have been shown to precede development of hypertension in
the general population, and there are indications that similar asso-
ciations are present in pregnancy (Cuevas, Williams, & Albert,
2017; Meng, Chen, Yang, Zheng, & Hui, 2012; Yan et al., 2015;
Zhang et al., 2013). There are several theorized biological
mechanisms supporting depression and/or anxiety as risk factors
for the development of hypertensive disorders, such as autonomic
dysregulation, neuroendocrine system disruption, and elevated
behavioral health risk factors (McEwen, 2007; Rouleau et al.,
2016; Strine et al., 2008; Winkel et al., 2015).
Results from several studies suggest that psychological distress,
broadly defined as unpleasant feelings, stress, or negative emo-
tions, is elevated in women with HDP. However, evidence from
meta-analyses examining associations between HDP and mental
health in pregnancy is limited by methodologic challenges of
the included studies: reliance on case-control methodology, retro-
spective designs, broad operational definitions of ‘distress’, restric-
tion to a single specific HDP (e.g. preeclampsia), or the inclusion
of HDP as one of many possible adverse perinatal outcomes
(Grigoriadis et al., 2013; Hu, Li, Zhang, & Yan, 2015; Zhang
et al., 2013). Given the increasing prevalence of HDP over the
last two decades (Wallis, Saftlas, Hsia, & Atrash, 2008) and the
potential for depression and anxiety in this population to be
both elevated and predictive of negative outcomes, a clarified
understanding of the associations between depression or anxiety
and the development of HDP is necessary.
Understanding the associations between depression and anx-
iety with hypertension during pregnancy could contribute to
improvements in screening and prevention of HDP, promote
future exploration of the mechanisms through which psycho-
logical factors influence HDP, and ultimately improve clinical
outcomes in this high-risk population (Henderson, Thompson,
Burda, & Cantor, 2017). As such, the objectives of the current
study were to: (1) determine the combined and independent asso-
ciations between clinically significant symptoms of depression or
anxiety or a diagnosis of a depression or anxiety disorder in preg-
nancy and HDP and (2) investigate whether the timing of onset
(i.e. prior to 20 weeks’ gestation) of clinically significant symp-
toms of depression or anxiety or a diagnosis of a depression or
anxiety disorder is an independent risk factor for HDP.
Methods
Inclusion and exclusion criteria
The methods for this review follow the PECOD framework
(Schardt, Adams, Owens, Keitz, & Fontelo, 2007). The population
of interest was pregnant women. Studies were included if they
assessed depression and/or anxiety as well as HDP. Depression
and anxiety were defined in two ways. First, scoring above the
recommended cut-offs on self-report depression or anxiety scales
with strong psychometric properties and agreement with gold
standard methods for psychological diagnostic criteria (e.g. a
structured clinical interview). Second, the presence of a clinical
diagnosis of depression (e.g. major depressive disorder) or anxiety
disorder (e.g. generalized anxiety disorder) using either the
Diagnostic and Statistical Manual of Mental Disorders, 5th
Edition (DSM-5) or the ICD-10 Classification of Mental and
Behavioural Disorders criteria determined using a diagnostic
interview or assessment and/or information available from
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medical record review. The terms ‘depression’ and ‘anxiety’ will
be used throughout the remainder of the paper to refer to the
above constructs. The outcome of interest was development of
HDP according to the standard clinical guidelines (Butalia
et al., 2018; Magee et al., 2018), which included any of the follow-
ing: gestational hypertension, pre-eclampsia, pre-eclampsia super-
imposed on chronic hypertension, and/or eclampsia. Women
were diagnosed with gestational hypertension or pre-eclampsia
if high blood pressure developed after 20 weeks’ gestation.
Women with pre-existing hypertension (also referred to as
chronic hypertension), defined as hypertension <20 weeks’ gesta-
tion, were excluded from this review wherever possible unless they
were later diagnosed with superimposed pre-eclampsia (using
standard criteria). As the criteria for HDP vary over time, stand-
ard definitions of HDP during the study time frame were used.
Studies were excluded if they were exclusively conducted on
participants that were known to have received active psychological
or pharmacological treatment to reduce their depression or anx-
iety during pregnancy and/or did not report data on an untreated
group. This was done to avoid confounding associations between
severity of depression and anxiety and HDP. Other exclusion cri-
teria included: using a proxy of psychological distress or a non-
validated mental health screening tool (e.g. single item questions);
mental health measurement/diagnoses that do not include depres-
sion or anxiety; not providing outcome information on HDP; and
study designs that were qualitative or case reports, conference
abstracts, or theses/dissertation work. These criteria also applied
to articles retrieved through hand-searching. Disagreement
regarding study eligibility was resolved by consensus.†1
Search strategy
Relevant literature was identified in two ways: first, a comprehen-
sive search of four electronic databases including Medline,
PsycINFO, Cumulative Index to Nursing and Allied Health
Literature (CINAHL), and Embase from database inception to
March 2020. Second, a hand search of reference lists from studies
that met inclusion criteria after full text review. Search criteria
were constructed collaboratively with a research librarian and
someone with expertise in the areas of psychology and pregnancy
(AM). The search terms included database specific controlled
vocabulary, field codes, operators, relevant keywords, and subject
headings. Studies were restricted to those published in English.
The search strategy and search terms are presented in online
Supplementary eTable 1 and eMethods.
Data extraction and quality assessment
After all relevant articles were identified using the databases and
duplicates removed using Covidence Systematic Review Software
(Veritas Health Innovation, http://www.covidence.org), two
reviewers (MS and ALM) independently screened the titles and
abstracts to determine eligibility for inclusion in full-text review.
Peer-reviewed observational studies that reported original data2
†
The notes appear after the main text.
1
When an inconsistency was noted, the two reviewers independently redid their review
and/or data extraction, and if the inconsistency remained, then the two reviewers would
discuss together to make a final decision.
2
Where multiple studies using data from the same larger cohort met inclusion criteria,
consensus was used to determine which would be included, based on having the largest
and least restricted sample (v. subgroup) and/or most recent publication date.
 Psychological Medicine
on depression and/or anxiety and HDP were retained for full-text
review, whereas non-human studies, case reports, reviews, editor-
ials, letters, dissertations, and books were excluded. Subsequently,
a full text review was conducted to determine eligibility for final
inclusion. The primary authors were contacted for studies that
had missing data. Data extraction was conducted independently
by two reviewers and discrepancies were resolved by consensus.
The following data were extracted: general study information, par-
ticipant ethnicity, depression and/or anxiety information and
measurement technique, and diagnosis of HDP. Data related to
sources of bias for quality assessment was also extracted.
Study quality was assessed using the Newcastle-Ottawa Scale
(NOS) component-based tool to identify sources of bias for observa-
tional studies including selection, detection, confounding, and attri-
tion. Total scores can range from 0 to 9, where higher scores reflect
higher quality and lower risk of bias. Although threshold scores have
yet to be established, previous meta-analyses have distinguished high
quality studies as those scoring 7–9 (Zhang et al., 2013).
Data analysis
A meta-analysis was conducted to determine the association
between depression and/or anxiety during pregnancy with HDP
using random-effects models to estimate the pooled relative risks
(RRs) and 95% confidence intervals (CIs) with Stata 16. Given
the possible variability across studies in measurement of depression
and anxiety, some degree of heterogeneity was anticipated and
assessed using I 2. The I 2 indicates the percentage of the variance
in study results that is due to heterogeneity between studies, rather
than due to chance, and is interpreted as low (25%), moderate
(50%), and high (75%) (Higgins, Thompson, Deeks, & Altman,
2003). Pre-specified stratified sensitivity analyses were conducted
to examine RR based on type of distress (depression or anxiety),
timing of the measurement of depression or anxiety (<20 weeks’
gestation v. >20 weeks), and on study quality.
This investigation follows the standards outlined by MOOSE
(Meta-analyses Of Observational Studies in Epidemiology) and was
registered with Prospero (Registration #CRD42018114230) through
the University of York Centre for Reviews and Dissemination.
Results
Literature search
As outlined in Fig. 1, the search resulted in 6291 articles.
Following removal of 2016 duplicates, 4275 papers were eligible
for title and abstract screening. After screening was completed,
a remaining 231 disagreements (94.6% agreement rate) were
resolved by consensus. There were 231 full text articles assessed
for eligibility with 35 studies meeting inclusion criteria. After
reviewing the reference lists of the included studies, another five
articles were deemed eligible for inclusion. Of the excluded
papers, 28 met inclusion criteria but did not report data on all
of the variables needed for analysis. Authors were contacted via
email, and four provided data that were then included in the
current analysis. Altogether, 44 studies were included.
Study characteristics
The 44 eligible studies, published between 2000 and 2020, had
samples ranging from 90 to 58 million participants (seven with
>10k, seven with >100k, and two with >1 million from medical
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3
registries), with a total of approximately 61 203 967 participants
included across the studies. In terms of hypertensive outcome,
14 studies evaluated pre-eclampsia, 5 examined gestational hyper-
tension, 25 used a combined outcome that included both gesta-
tional hypertension and pre-eclampsia or broadly categorized all
cases as ‘HDP’.
In terms of mental health variables, studies focusing on
depression alone were the most common (n = 23), followed by a
combination of depression and anxiety (n = 11), anxiety alone
(n = 8), and anxiety, depression, or other disorder (n = 2).
Depression or anxiety was assessed by: using self-report question-
naires (n = 22), medical chart reviews (n = 20), or structured diag-
nostic clinical interviews (n = 3) (Table 1).
Many studies considered other relevant covariates in addition to
body mass index (BMI). For example, several studies included socio-
demographic information (e.g. maternal age, ethnicity, education,
income, and marital status), obstetrical information (e.g. parity,
pregnancy complications, and gestational age), health-related beha-
viors (e.g. tobacco use), and health information such as diabetes
(including gestational), previous history of hypertension (including
pregnancies), and anti-depressant/anxiolytic medication use.
Associations between depression and/or anxiety and
hypertensive disorders of pregnancy
Overall, as outlined in Fig. 2, exposure to clinically significant symp-
toms of depression or anxiety or a diagnosis of a depression or anx-
iety disorder in pregnancy was associated with a higher likelihood of
a diagnosis of HDP. There was an overall increased RR of 39% for
HDP with exposure to prenatal depression or anxiety at any time
during pregnancy (RR = 1.39; 95% CI 1.25–1.54; 44 studies).
Type of distress and risk for hypertensive disorders of
pregnancy
Several studies specifically investigated either depression or anxiety
as an exposure or reported results for anxiety and depression separ-
ately, allowing for stratified analysis by type of distress. When
restricted to studies investigating depression (Avalos, Chen, & Li,
2015; Bandoli & Chambers, 2017; Cripe, Frederick, Qiu, &
Williams, 2011; Dayan et al., 2006; De Vera & Bérard, 2012;
Goedhart et al., 2010; Henrichs et al., 2010; Hermon, Wainstock,
Sheiner, Golan, & Walfisch, 2019; Heun-Johnson et al., 2019;
Ibanez et al., 2012; Katon, Russo, Melville, Katon, & Gavin, 2012;
Khanghah, Khalesi, & Rad, 2020; Kim et al., 2013; Kurki,
Hiilesmaa, Raitasalo, Mattila, & Ylikorkala, 2000; Lutsiv et al.,
2015; Mogos et al., 2019; Navaratne, Foo, & Kumar, 2016; Packer,
Pilliod, Chatroux, Caughey, & Valent, 2019; Palmsten, Setoguchi,
Margulis, Patrick, & Hernández-Díaz, 2012; Qiu, Sanchez, Lam,
Garcia, & Williams, 2007; Ruiz et al., 2012; Schmidt et al., 2019;
Suri et al., 2007; Venkatesh, Ferguson, Smith, Cantonwine, &
McElrath, 2019; Yedid Sion, Harlev, Weintraub, Sergienko, &
Sheiner, 2016; Yonkers, Gilstad-Hayden, Forray, & Lipkind, 2017),
results indicated an increased risk of HDP (RR = 1.30; 95% CI
1.19–1.43; 26 studies). Analysis of studies on anxiety (Avraham,
Tamar, Eyal, & Gali, 2020; Bánhidy, Ács, Puhó, & Czeizel, 2006;
Catov, Abatemarco, Markovic, & Roberts, 2010; Chen, Lin, & Lee,
2010; De Vera & Bérard, 2012; Garza-Veloz et al., 2017; Ibanez
et al., 2012; Kordi, Vahed, Rezaee, Reza, & Lotfalizadeh, 2017;
Pavlov, Steiner, Kessous, Weintraub, & Sheiner, 2014; Ravid et al.,
2018) also indicated an increased risk of HDP (RR = 1.49; 95% CI
1.13–21.98; 10 studies).
 4 Matthew Shay et al.

Fig. 1. Flow diagram.

Timing of depression or anxiety as a risk factor for
hypertensive disorders of pregnancy
As HDP are diagnosed after 20 weeks’ gestation, we next looked
at the 17 studies that examined the onset/diagnosis of clinically
significant symptoms or a diagnosis of depression mood or an
anxiety disorder in pregnancy prior to 20 weeks’ gestation
(Avalos et al., 2015; Bandoli & Chambers, 2017; Catov et al.,
2010; Cripe et al., 2011; De Vera & Bérard, 2012; Garza-Veloz
et al., 2017; Goedhart et al., 2010; Henrichs et al., 2010;
Ibanez et al., 2012; Kim et al., 2013; Kurki et al., 2000; Lang
et al., 2019; Lutsiv et al., 2015; Palmsten et al., 2012; Suri

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Psychological Medicine
Table 1. Characteristics of included studiesa

Sample Quality
Source Country size Race/ethnicity Type of distress Timing of distress Measure of distress Diagnosis of HDP rating

Avalos et al. (2015) USA 21 589 36.4% White, 30.7% Asian, 24.3% Hispanic, 5.1% Black, Depression 6 months before Diagnosis or PHQ-9 ⩾ 10 from PE: ICD-9 diagnosis from medical 8
3.6% Other/unknown pregnancy to 20 weeks’ medical record record
gestation

Avraham et al. (2020) Israel 242 342 47.4% Jewish Anxiety Before or during ICD-9 diagnosis from medical HDP: ICD-9 diagnosis from medical 7
pregnancy record record

Bandoli and Canada and 3034 77.1% White, 12.3% Hispanic, 4.3% Black, 6.3% Asian/ Depression 0–34 weeks’ gestation Self-report of diagnosis PE self-report and medical record 6
Chambers (2017) USA Other (criteria NR)

Bánhidy et al. (2006) Hungary 38 151 NR (100% White) Anxiety Pregnancy Diagnosis from medical PE from medical record (criteria NR) 4
record

Bernard et al. (2019) Canada 6878 96.9% White Anxiety and Pregnancy Diagnoses from medical HDP: SOGC diagnosis from medical 8
depression record record

Brown et al. (2016) Canada 382 774 NR Mental illness Within 2 years before ICD-9/10 diagnosis from PE/GH from medical record (criteria 5
pregnancy medical record NR)

Catov et al. (2010) USA 667 70.0% White, 30.0% Black Anxiety 18 weeks’ gestation STAI > 20 PE: BP > 140/90 and proteinuria 6

Chen et al. (2010) Taiwan 1902 NR Anxiety Within 2 years before and ICD-9 diagnosis from medical PE from medical record (criteria NR) 6
during pregnancy record

Cripe et al. (2011) USA 3432 86.3% White Depression/ Before pregnancy to 20 Diagnosis from medical HDP: ACOG criteria from medical 8
anxiety weeks’ gestation record record

Dayan et al. (2006) France 681 94.2% White, 5.8% Other Depression 20–28 weeks’ gestation EPDS ⩾ 14 GH: BP ⩾ 140/90 from medical record 7

De Vera and Bérard Canada 13 376 NR Depression/ History ICD-9 diagnosis from medical HDP: ICD-9 diagnosis from medical 7
(2012) anxiety record record

Garza-Veloz et al. Mexico 321 NR Anxiety 20 weeks’ gestation GHQ > 6/7 HDP: ISSHP(7) criteria from medical 4
(2017) record

Goedhart et al. Netherlands 8050 53.0% Dutch, 8.6% Moroccan, 8.0% Creole, 5.0% Depression 2 weeks after first prenatal CES-D ⩾ 16 HDP from medical record (criteria NR) 7
(2010) Turkish, 25.4% Other visit or self-report high BP/medication

Hendryx et al. (2020) Australia 9075b 88.6% Australian, 3.6% Asian, 1.6% Indigenous Depression/ During pregnancy Self-report GH from self-report 5
anxiety

Henrichs et al. (2010) Netherlands 6313 52.6% Dutch, 11.9% Other Western, 8.8% Surinamese, Depression 19–21 weeks’ gestation BSI top 15% PE/GH from medical record (criteria 7
8.4% Turkish, 5.5% Moroccan, 3.9% Cape Verdian, NR)
3.4% Dutch Antilles, 5.5% Other

Hermon et al. (2019) Israel 279 57.0% Jewish, 36.2% Bedouin Depression ⩾24 weeks’ gestation EPDS ⩾ 10 PE from medical record 3

Heun-Johnson et al. USA 5 518 766 47.2% White, 19.6% Hispanic, 12.6% Black, 4.8% Asian, Depression During pregnancy MDD: ICD-9 diagnosis from HDP: ICD-9 diagnosis from medical 7
(2019) 0.7% Indigenous, 15.1% Other/Unknown medical record record

Horsley et al. (2019) Canada 2763 79.3% White, 10.5% Asian, 2.2% Hispanic, 0.8% Depression/ <25 weeks’ gestation EPDS ⩾ 10/STAI ⩾ 40 HDP: ICD-10 diagnosis from medical 8
Indigenous, 5.6% Other anxiety record

Ibanez et al. (2012) France 2002 NR Depression/ <20 weeks’ gestation CES-D ⩾ 16/STAI-S ⩾ 37 GH from medical record (criteria NR) 7
anxiety

Katon et al. (2012) USA 2577 65.3% White Depression 20–30 weeks’ gestation PHQ-9 and/or antidepressant HDP: ICD-9 diagnosis from medical 6
use record

Khanghah et al. Iran 394 NR Depression 20–28 weeks’ gestation CES-D > 15 PE: self-report (criteria NR) 3
(2020)
(Continued)

5
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Table 1. (Continued.)

6
Sample Quality
Source Country size Race/ethnicity Type of distress Timing of distress Measure of distress Diagnosis of HDP rating

Kim et al. (2013) USA 261 100% Black Depression 6–38 weeks’ gestation EPDS ⩾ 10 PE: hypertension and proteinuria 5
from medical record

Kordi et al. (2017) Iran 300 NR Anxiety 28–40 weeks’ gestation DASS-21 ⩾ 8 PE: BP ⩾ 140/90 and proteinuria 5

Kurki et al. (2000) Finland 623 100% White Depression First prenatal visit Shortened BDI > 3 PE: BP > 140/100 and proteinuria 5

Lang et al. (2019) China 5661 NR Depression/ 11–12 weeks’ gestation SDS ⩾ 53/SAS ⩾ 50 HDP: GH (140/90), PE (GH and 6
anxiety proteinuria), eclampsia (PE and
convulsions)

Lutsiv et al. (2015) Canada 70 605 NR Depression Current or previous Self-report of diagnosis from GH/PE from medical record (criteria 7
pregnancy medical chart NR)

Malm et al. (2015) Finland 56 775 NR Mental illness 1 year before and during ICD diagnosis from medical HDP from medical record (criteria NR) 7
pregnancy record

Mogos et al. (2019) USA >58 M 42.1% White, 18.8% Hispanic, 11.9% Black, 8.6% Depression Delivery discharge ICD-9 diagnosis from medical HDP: ICD-9 diagnosis from medical 6
Other, 18.7% Unknown record record

Navaratne et al. Australia 26 110 62.1% White, 18.9% Asian, 2.2% Indigenous, 16.7% Depression <20 weeks’ gestation EPDS ⩾ 12 HDP from medical record (criteria NR) 5
(2016) Other

Packer et al. (2019) USA 170 572 57.4% Hispanic, 36.2% Black, 19.3% Asian, 18.9% Depression Pregnancy ICD-9 diagnosis from medical PE and GH: ICD-9 from medical record 7
White record

Palmsten et al. Canada 306 831 NR Depression 1 year before to 20 weeks’ ICD-9 diagnosis from medical PE: ICD-9 diagnosis 7
(2012) gestation record

Pavlov et al. (2014) Israel 256 312 50.4% Bedouin, 49.6% Jewish Anxiety Pregnancy Diagnosis from medical GH from medical record (criteria NR) 6
record

Qiu et al. (2007) Peru 676 NR Depression Pregnancy PHQ-9 Moderate = 10–14/ PE: BP > 140/90 and proteinuria 8
moderate–severe = 15–19

Ravid et al. (2018) Israel 512 NR (94.3% local birth) Anxiety 24–40 weeks’ gestation STAI-T > 38 HGH/PE: ACOG criteria 4

Rejnö et al. (2019) Sweden 950 301 NR (95.7% born in Nordic countries, 4.3% other) Anxiety and 1 year before pregnancy ICD-9 diagnosis or PE from medical record (criteria NR) 8
depression to delivery prescription from medical
record

Ruiz et al. (2012) USA 407 100% Hispanic Depression 22–24 weeks’ gestation CES-D > 16 PE from medical record (criteria NR) 6

Schmidt et al. (2019) Netherlands 100 37.0% Moroccan, 29.0% Dutch, 16.0% Turkish, 7.0% Depression 28–32 weeks and/or 33–37 PHQ-9 ⩾ 12 GH from self-report 4
Surinamese, 11.0% Other weeks’ gestation

Suri et al. (2007) USA 90 NR Depression Pregnancy SCID HDP (criteria NR) 6

Suzuki et al. (2015) Japan 9461 100% Asian Depression/ Before and during Diagnosis from medical GH: BP ⩾ 140/90 from medical record 7
anxiety pregnancy record

Thombre Kulkarni USA 12 647 90.3% White, 4.4% Black, 5.3% Other Depression/ 2 years before pregnancy ICD-9 diagnosis in medical HDP: ICD-9 diagnosis from medical 8
et al. (2019) anxiety to delivery record record

Venkatesh et al. USA 433 59.3% White, 16.5% Black, 13.1% Hispanic, 11.1% Depression Pregnancy Diagnosis from medical GH and PE (criteria NR) 6

Matthew Shay et al.

(2019) Other record

Winkel et al. (2015) Germany 283 NR Depression/ Onset before pregnancy CIDI-V GH: BP ⩾ 140/90 from medical record 9
anxiety

Yedid Sion et al. Israel 256 312 NR Depression Before gestation Diagnosis from medical PE from medical record (criteria NR) 5
(2016) record
(Continued)
 Psychological Medicine 7

Classification of Diseases; SOGC, Society of Obstetricians and Gynaecologists of Canada; STAI, State Trait Anxiety Inventory; ACOG, American College of Obstetricians and Gynecologists; EPDS, Edinburgh Postnatal Depression Scale; GHQ, General Health
Questionnaire; ISSHP, International Society for the Study of Hypertension in Pregnancy; CES-D, Center for Epidemiological Studies-Depression scale; BSI, Brief Symptom Inventory; DASS, Depression, Anxiety, and Stress Scale; BDI, Beck Depression
et al., 2007; Suzuki, Shinmura, & Kato, 2015; Winkel et al.,
Quality

2015) in order to determine if depression or anxiety preceded

rating

NR, not reported; HDP, hypertensive disorders of pregnancy; PE, pre-eclampsia; GH, gestational hypertension; OR, odds ratio; RR, relative risk; CI, confidence interval; BP, blood pressure; PHQ, Patient Health Questionnaire; ICD, International
8
the diagnosis of HDP. Results of the analysis showed an
increased risk of HDP in women who received a diagnosis or
had self-reported clinically significant symptoms of depression
or an anxiety in pregnancy before 20 weeks’ gestation (RR =
GH/PE from medical record

1.27; 95% CI 1.07–1.50).3

Diagnosis of HDP

Study quality
Finally, we analyzed studies based on methodologic quality. The
average study score was 6.23 (S.D. = 1.46, range = 3–9; online
Supplementary eTable 2), with 21 studies deemed ‘high quality’
(⩾7). Both high (RR = 1.28; 95% CI 1.16–1.43) and low (RR =
1.51; 95% CI 1.21–1.88) quality studies showed an increased risk
Measure of distress

of HDP in women who received a diagnosis or self-reported clin-

Inventory; SDS, Self-rating Depression Scale; SAS, Self-rating Anxiety Scale; SCID, Structured Clinical Interview for DSM; CIDI, Composite International Diagnostic Interview for Women.

ically significant symptoms of depression and/or anxiety in preg-

nancy. Meta-regression comparing high v. low quality studies
produced a non-significant result (b = −0.14, p = 0.28).
Meta-analysis results based on stratification are reported in Table 2.
Each row in this table describes an independent study that examined prenatal depression and/or anxiety and HDP. ; NOS study quality ratings can range from 0 to 9.
CIDI

Heterogeneity
<17 weeks and/or 28
Timing of distress

There was significant heterogeneity in the included studies, as

weeks’ gestation

indicated by an I 2 value of 97.0% on the full sample. When

depression or anxiety were measured in early pregnancy, hetero-
geneity decreased to an I 2 value of 83.5%, suggesting that some of
the heterogeneity may related to gestational age at data collection.
Similarly, restricting analysis to studies investigating a single con-
struct such as depression (I 2 = 88.4%, p < 0.001) or anxiety (I 2 =
Depression/

72.4%, p < 0.001) also show lowered heterogeneity values.

Type of
distress

anxiety

Publication bias
A funnel plot showed slight asymmetry, but overall did not suggest
73.7% White, 14.4% Hispanic, 7.3% Black, 4.5%

publication bias (online Supplementary eFig. 1). There were few

data points suggesting significant risk associated with depression or
anxiety in papers with high standard error and low sample size
(e.g. lower right side). Correspondingly, Egger’s test for small-study
Race/ethnicity

effects was non-significant (b = −0.00, [−1.88 to 1.88], p = 0.99;

online Supplementary eFig. 2). Similarly, Begg’s rank correlation
between standardized intervention effect and standard error (z =
1.34, p = 0.18) was non-significant. Although not definitive,
Data for analysis taken from larger cohort after consultation with authors.

altogether these results indicate a low likelihood of an association

between sample size, effect size, and the presence of publication
bias in the included studies.
Other

Discussion
Sample
size

The primary aim of this systematic review and meta-analysis was

2654

to synthesize literature showing associations between depression

and/or anxiety with HDP. Three main findings were observed.
Country

First, in the overall meta-analysis of over 61.2 million pregnancies

across 44 studies, women with clinically elevated symptoms or a
USA

diagnosis of depression and/or anxiety during pregnancy had

an increased RR of 39% for diagnosis of an HDP compared to
Table 1. (Continued.)

the non-exposed group. Second, subgroup analysis examining

Yonkers et al.

associations between depression and anxiety assessed prior to

Source

(2017)

3
Due to three studies including definitions of HDP that may have included cases of
chronic or pre-existing hypertension that pre-dated 20 weeks gestation, a separate analysis
was conducted with these studies removed (RR = 1.25; 1.05–1.49).
b
a

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 8 Matthew Shay et al.
Fig. 2. Forest plot of RR of HDP in women exposed to depression and/or
anxiety in pregnancy.
20 weeks of gestation and diagnosis of HDP also showed an asso-
ciation, such that women who experienced depression or anxiety
early in their pregnancies had an increased RR of later diagnosis
of HDP compared to non-exposed pregnancies. Finally, when
depression and anxiety were investigated separately, they were
each independently associated with greater risk of receiving an
HDP diagnosis compared to a non-exposed group.
When restricting the analyses to studies that measured depres-
sion or anxiety early in pregnancy (<20 weeks), prior to the diag-
nosis of the types of HDPs, the risk of HDP associated with
prenatal depression and/or anxiety remained significant. By
restricting analysis prior to diagnosis, recall bias associated with
negative obstetric outcomes is removed (Hamilton & Gotlib,
2008). The findings suggest that depression and anxiety may
increase the risk for the development of HDP and point to the
potential for future research to focus on depression and anxiety
in populations at risk for HDP.
A slightly higher risk of HDP was found in the studies focus-
ing on anxiety as opposed to those focused on depression.
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Although there is some evidence linking physiological mechan-
isms of hypertension to anxiety specifically (for a review, see
Johnson, 2019), there is also strong evidence that both anxiety
and depression have common and unique contributions to mea-
surements of cardiovascular health (Firulescu, May, Ferrer,
Fincham, & Sanchez-Gonzalez, 2017). The high comorbidity
and symptom overlap between depression and anxiety suggests
that even in studies where anxiety or depression alone is the
focus, there likely remains some unmeasured overlap (Moffitt
et al., 2007). Furthermore, there were more studies included in
our analysis that focused on depression, making it difficult to
draw any firm conclusion regarding differential risk of depression
or anxiety in this analysis. Overall, pregnant women with either
depression or anxiety appear to have a higher prevalence of HDP.
The connection between depression and anxiety in pregnancy
with HDP could be explained several ways. Depression and/or
anxiety during pregnancy may be associated with hypertensive
outcomes through a disruption to autonomic nervous system
activity such as heightened sympathetic activity (Schobel,
 Psychological Medicine 9

Table 2. Summary of results of stratified meta-analyses

Study stratification No. of studies RR 95% CI I 2 (%)

Full sample 44 1.39 1.25–1.54 97.0

Distress exposure <20 weeks 17 1.27 1.07–1.50 83.5
Depression 26 1.30 1.19–1.43 88.4
Anxiety 10 1.49 1.13–1.98 72.4
High quality studies (⩾7 on NOS) 21 1.28 1.16–1.43 91.2
Low quality studies (<6 on NOS) 23 1.51 1.21–1.88 91.8
Pre-eclampsia only 15 1.32 1.14–1.52 90.8
Gestational hypertension only 4 1.26 0.72–2.19 91.8
Any/all HDP 25 1.46 1.24–1.73 97.9
Self-reported mental health questionnaires 21 1.37 1.13–1.65 79.0
Depression/anxiety disorder diagnosis pulled from medical record 20 1.40 1.22–1.61 98.6
Structured clinical diagnostic interview for depression/anxiety 3 1.64 1.08–2.48 0
NOS, The Newcastle-Ottawa Scale; RR, relative risk; HDP, hypertensive disorders of pregnancy.

Fischer, Heuszer, Geiger, & Schmieder, 1996). During pregnancy,
the cardiovascular system undergoes prominent changes as blood
pressure and heart rate adjust to accommodate fetal growth
(Grindheim, Estensen, Langesaeter, Rosseland, & Toska, 2012;
Mastrobattista & Monga, 2018), and the sympathetic nervous sys-
tem has been identified as a possible mediator between stress and
cardiovascular disease (Hering, Lachowska, & Schlaich, 2015).
Furthermore, depression or anxiety in pregnancy may also
cause physiological changes responsible for hypertensive out-
comes through shared physiological mechanisms between mood
and blood pressure regulation (Sandman, Wadhwa, Chicz-DeMet,
Dunkel-Schetter, & Porto, 1997). Finally, behavioral risk factors
associated with depression and anxiety, including lowered physical
activity (Schuch et al., 2017), increased substance use (Lai, Cleary,
Sitharthan, & Hunt, 2015), and poor sleep (Tomfohr, Buliga,
Letourneau, Campbell, & Giesbrecht, 2015), may also increase the
risk of HDP. Therefore, depression and anxiety may not operate
as causal factors in the development of HDP, but may reflect an
early indication of a vulnerability to the development of hyperten-
sion. It is also possible that the discussed mechanisms, including
physiological and behavioral risk factors, may represent a shared
pathway to both depression and/or anxiety as well as HDP. The
links between mental health and obstetrical outcomes is an emer-
ging area, and there is increasing evidence that there may be a
cumulative impact of depression and/or anxiety on negative obstet-
rical outcomes. Specifically, studies have suggested that pregnant
women with a diagnosis of anxiety in addition to hypertension
are at higher risk of preterm delivery than women with hyperten-
sion alone (Hilmert et al., 2008; Horsley et al., 2019). Fortunately,
clinical interventions such as cognitive behavioral therapy during
pregnancy have been demonstrated to effectively prevent and reduce
prenatal depression and anxiety (Curry et al., 2019; Marchesi et al.,
2016). Guidelines endorsed by numerous countries now recom-
mend screening and treatment for depression and anxiety during
the perinatal period (Austin & Highet, 2017; Williams, 2014).
Timely identification and treatment of maternal depression and
anxiety in pregnancy have the potential to not only reduce the
development of HDP but may further minimize the psychological
impact of HDP.
Strengths and limitations
This study represents the most current and comprehensive litera-
ture investigating the association between prenatal depression and
anxiety with HDP to date. Results were robust across study quality
and the risk of publication bias was low. The search strategy was
predefined and comprehensive. The review expanded upon previ-
ous meta-analytic work in this area by including all types of
HDPs as the outcome, as well as restricting the definition of the
exposure to psychometrically valid and reliable self-report scales
or using DSM and ICD diagnoses present in the health record
for depression and/or anxiety. The use of specific diagnostic cri-
teria for depression and anxiety is a strength of the current ana-
lysis, providing a foundation for identifying evidence-based
interventions that can reduce or prevent the experience of the psy-
chological distress.
Several limitations should be noted. The current analysis was
restricted to the inclusion of English language papers, though
this is unlikely to have markedly impacted the overall study find-
ings (Hartling et al., 2017). Furthermore, diagnostic criteria sur-
rounding measurement of hypertension have changed during
the course of publication of the studies included in this analysis,
with a lowering of the threshold for hypertension in the general
population in 2017 (Whelton & Carey, 2017). This could change
the number of women diagnosed with pre-existing hypertension
and alter the overall prevalence of hypertensive disorders in preg-
nancy in more recent studies. The diagnostic criteria for HDP
were also updated in 2013 by the American College of
Obstetrics and Gynecology, and studies conducted before this
time may therefore be under-reporting prevalence if current
guidelines were to be applied (American College of
Obstetricians and Gynecologists, 2013). Reporting across the
included studies did not consistently allow for the exclusion of
cases of chronic hypertension that were categorized more broadly
as HDP. Although our goal was to investigate new incidence of
hypertension during pregnancy, it was not always possible to con-
firm that no cases of chronic hypertension were included under
the umbrella of HDP. Not all studies were published with HDP
as the outcome of interest. Therefore, they did not systematically

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 10
provide information on anti-hypertensive medication or pre-
existing cardiovascular risk factors or known diseases, nor did
we request or collect this information. In general, given the
young age of the populations studied the prevalence of cardiovas-
cular risk factors is generally low. Similarly, we were unable to
consistently examine the impact of aspirin, an evidence-based
intervention to reduce the risk of HDP, across all included studies.
Although mood disorders are not a current recommended indica-
tion for use of ASA, this study is unable to comment on the use of
ASA in this population and the effects of ASA on incidence of
HDP in women with mood disorders. Additionally, less than
50% of the included studies were found to be high quality,
although our analysis comparing high- and low-quality studies
was non-significant and suggests that results did not differ
based on study quality. In addition, several studies (11) had
exposure ranges that could potentially include pre-conception
depression and/or anxiety. Although participants experiencing
depression or anxiety before conception likely continued to
meet criteria during the prenatal period (Bayrampour, Tomfohr,
& Tough, 2016), their risk of developing HDP could differ from
those with onset during the first 20 weeks of gestation. Finally,
observational research presents difficulties for drawing firm
causative conclusions and alternative explanations for the rela-
tionship described in the current review between maternal mental
health and HDP may exist.
Overall, there was high heterogeneity across included studies,
likely owing to variation in definition and assessment of depres-
sion, anxiety, and HDP. The HDP outcomes reported varied by
study and these variations represent important clinical distinc-
tions in the severity of HDP. Pre-eclampsia generally represents
the more severe condition, with stronger associations with mater-
nal morbidity and mortality than gestational hypertension
alone (Say et al., 2014). Consequently, the overall health profiles
of the women included in studies specifically examining pre-
eclampsia may differ from those investigating other HDP.
Additionally, the method used to measure depression and/or
anxiety may influence rates of detection. Several studies focused
on medical chart review to determine the presence of depres-
sion and/or anxiety. Without integrated and systematic use of
validated screening tools, it is possible that many women
with meaningful psychological symptoms were not accurately
diagnosed or did not have their mental health assessed or
recorded by their physicians, potentially underrepresenting
the association between these disorders and HDP (Milgrom
& Gemmill, 2014).
In addition to measurement variation, there are other pos-
sible sources of heterogeneity including geographic location
and race/ethnicity of participants. Included studies were con-
ducted in 16 different countries. Despite the apparent strength
of this diverse geographical representation, there were 21 studies
consisting of a predominantly White sample. Furthermore, 18
did not explicitly report any demographic data on race or ethni-
city. Therefore, findings may be limited by possible racial/ethnic
bias across the included studies. Future projects should prioritize
diverse and representative samples and make an effort to recruit
from under-represented populations to ensure that findings are
broadly relevant across groups. Previous research has suggested
that ethnicity may be a contributing factor in the relationship
between prenatal psychological distress of HDP, with lower
risk in European and Asian countries than in other parts of
the world (Shen, Tymkow, Macmullen, & Utcomes, 2005;
Zhang et al., 2013).
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Matthew Shay et al.
Ultimately, the high heterogeneity in the current analysis may
be a strength of the findings. The ability to detect an association
between HDP and prenatal depression and/or anxiety across var-
iations in psychological measurement methods, hypertension
severity, patient ethnicity, and study design suggest a persistent
association, reinforces the importance of this relationship and
warrants further consideration.
Conclusion
Results of this systematic review and meta-analysis established the
independent associations between prenatal depression and/or
anxiety at any time during pregnancy and HDP and also demon-
strated that the onset of depression and/or anxiety prior to 20
weeks’ gestation is a risk factor for development of HDP. Given
overall prevalence estimates of HDP, baseline risk for HDP is
10–15% (Regitz-Zagrosek et al., 2011; Umesawa & Kobashi,
2017). Results of this meta-analysis indicate that there is up to
a 40% increase in risk of HDP in women experiencing depression
and/or anxiety at any time during pregnancy and an almost 30%
increase in those who experience depression or anxiety early in
pregnancy. Health care providers should be alert to mental health
concerns among women ultimately diagnosed with HDP. Greater
attention to common mental health disorders during pregnancy is
necessary to identify, support, and treat women at risk of or who
have been diagnosed with HDP.
Supplementary material. The supplementary material for this article can
be found at https://doi.org/10.1017/S0033291720003062.
Author contributions.
Abstract screening, full text review, data extraction, and data analysis completed by MS
and ALM. AM assisted in creating search terms. All authors contributed to the writing
and revisions of manuscript text.
Financial support. This work was supported by the generous donors of the
Alberta Children’s Hospital Foundation (LTM and ST), a career development
award from the Canadian Child Health Clinician Scientist Program (LTM), the
Canadian Institute of Health Research (CIHR; LTM), and the Social Sciences
and Humanities Research Council (SSHRC; LTM and ST), a Heart and Stroke
(Alberta) new investigator award (KN), a CIHR New Investigator Award
(AM), an Alberta Children’s Hospital Research Institute Postdoctoral
Fellowship and Cumming School of Medicine Postdoctoral Scholarship
(ALM), Alberta Innovates Health Solutions and MaxBell Foundation (ST).
Funds were received competitively and did not influence the research.
Conflict of interest. No conflicts of interest were reported.
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