Hypertensive disorders of pregnancy (HDP) represent a broad spectrum of disorders ranging from gestational hypertension and chronic hypertension to non-severe pre-eclampsia (including 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., Reference Butalia, Audibert, Côté, Firoz, Logan, Magee and Nerenberg2018; Magee et al., Reference Magee, Kenny, Karumanchi, Mccarthy, Saito, Hall and Mohammed2018). Occurring in approximately 10–15% of pregnancies (Umesawa & Kobashi, Reference Umesawa and Kobashi2017), HDP alter in-utero fetal growth conditions and are associated with elevated risk for preterm birth and increased long-term vascular, psychiatric, and neurodevelopmental outcomes in infants (Maher et al., Reference Maher, O'Keeffe, Kearney, Kenny, Dinan, Mattsson and Khashan2018; Regitz-Zagrosek et al., Reference Regitz-Zagrosek, Blomstrom Lundqvist, Borghi, Cifkova, Ferreira, Foidart and Warnes2011). 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, Reference Filippi, Chou, Ronsmans, Graham, Say, Black, Laxminarayan, Temmerman and Walker2016; Say et al., Reference Say, Chou, Gemmill, Tunçalp, Moller, Daniels and Alkema2014).
Depression and anxiety are common during pregnancy, with greater than 10% of women reporting clinically significant symptoms of depression and more than 30% reporting significant anxiety (Leach, Poyser, & Fairweather-Schmidt, Reference Leach, Poyser and Fairweather-Schmidt2017; Tebeka, Le Strat, & Dubertret, Reference Tebeka, Le Strat and Dubertret2016). Prenatal depression and/or anxiety are risk factors for a number of obstetric complications and strong predictors of postpartum mental health problems (Alder, Fink, Bitzer, Hösli, & Holzgreve, Reference Alder, Fink, Bitzer, Hösli and Holzgreve2007; Underwood, Waldie, D'Souza, Peterson, & Morton, Reference Underwood, Waldie, D'Souza, Peterson and Morton2016). Emerging evidence 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., Reference Hilmert, Schetter, Dominguez, Abdou, Hobel, Glynn and Sandman2008; Horsley, Tomfohr-Madsen, Ditto, & Tough, Reference Horsley, Tomfohr-Madsen, Ditto and Tough2019), with one recent study reporting that reduced gestational age is associated with HDP at all percentiles of self-reported depression or anxiety symptoms (Horsley et al., Reference Horsley, Tomfohr-Madsen, Ditto and Tough2019). 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 associations are present in pregnancy (Cuevas, Williams, & Albert, Reference Cuevas, Williams and Albert2017; Meng, Chen, Yang, Zheng, & Hui, Reference Meng, Chen, Yang, Zheng and Hui2012; Yan et al., Reference Yan, Pan, Cai, Cheng, Dong, An and Wang2015; Zhang et al., Reference Zhang, Ding, Liu, Chen, Wu, Zhang and Yu2013). 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, Reference McEwen2007; Rouleau et al., Reference Rouleau, Tomfohr-Madsen, Campbell, Letourneau, O'Beirne, Giesbrecht and Team2016; Strine et al., Reference Strine, Mokdad, Dube, Balluz, Gonzalez, Berry and Kroenke2008; Winkel et al., Reference Winkel, Einsle, Pieper, Höfler, Wittchen and Martini2015).
Results from several studies suggest that psychological distress, broadly defined as unpleasant feelings, stress, or negative emotions, 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, retrospective designs, broad operational definitions of ‘distress’, restriction to a single specific HDP (e.g. preeclampsia), or the inclusion of HDP as one of many possible adverse perinatal outcomes (Grigoriadis et al., Reference Grigoriadis, VonderPorten, Mamisashvili, Tomlinson, Dennis, Koren and Ross2013; Hu, Li, Zhang, & Yan, Reference Hu, Li, Zhang and Yan2015; Zhang et al., Reference Zhang, Ding, Liu, Chen, Wu, Zhang and Yu2013). Given the increasing prevalence of HDP over the last two decades (Wallis, Saftlas, Hsia, & Atrash, Reference Wallis, Saftlas, Hsia and Atrash2008) 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 anxiety with hypertension during pregnancy could contribute to improvements in screening and prevention of HDP, promote future exploration of the mechanisms through which psychological factors influence HDP, and ultimately improve clinical outcomes in this high-risk population (Henderson, Thompson, Burda, & Cantor, Reference Henderson, Thompson, Burda and Cantor2017). As such, the objectives of the current study were to: (1) determine the combined and independent associations between clinically significant symptoms of depression or anxiety or a diagnosis of a depression or anxiety disorder in pregnancy and HDP and (2) investigate whether the timing of onset (i.e. prior to 20 weeks' gestation) of clinically significant symptoms 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, Reference Schardt, Adams, Owens, Keitz and Fontelo2007). 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 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., Reference Butalia, Audibert, Côté, Firoz, Logan, Magee and Nerenberg2018; Magee et al., Reference Magee, Kenny, Karumanchi, Mccarthy, Saito, Hall and Mohammed2018), which included any of the following: gestational hypertension, pre-eclampsia, pre-eclampsia superimposed 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' gestation, 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, standard 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 anxiety 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 criteria 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 depression 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.Footnote †Footnote 1
Search strategy
Relevant literature was identified in two ways: first, a comprehensive 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 dataFootnote 2 on depression and/or anxiety and HDP were retained for full-text review, whereas non-human studies, case reports, reviews, editorials, 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, participant 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 observational studies including selection, detection, confounding, and attrition. 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., Reference Zhang, Ding, Liu, Chen, Wu, Zhang and Yu2013).
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, Reference Higgins, Thompson, Deeks and Altman2003). 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.
Fig. 1. Flow diagram.
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 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 hypertension, 25 used a combined outcome that included both gestational 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 questionnaires (n = 22), medical chart reviews (n = 20), or structured diagnostic clinical interviews (n = 3) (Table 1).
Table 1. Characteristics of included studiesa
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 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 Inventory; SDS, Self-rating Depression Scale; SAS, Self-rating Anxiety Scale; SCID, Structured Clinical Interview for DSM; CIDI, Composite International Diagnostic Interview for Women.
a 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.
b Data for analysis taken from larger cohort after consultation with authors.
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 behaviors (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 symptoms of depression or anxiety or a diagnosis of a depression or anxiety 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).
Fig. 2. Forest plot of RR of HDP in women exposed to depression and/or anxiety in pregnancy.
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 separately, allowing for stratified analysis by type of distress. When restricted to studies investigating depression (Avalos, Chen, & Li, Reference Avalos, Chen and Li2015; Bandoli & Chambers, Reference Bandoli and Chambers2017; Cripe, Frederick, Qiu, & Williams, Reference Cripe, Frederick, Qiu and Williams2011; Dayan et al., Reference Dayan, Creveuil, Marks, Conroy, Herlicoviez, Dreyfus and Tordjman2006; De Vera & Bérard, Reference De Vera and Bérard2012; Goedhart et al., Reference Goedhart, Snijders, Hesselink, Van Poppel, Bonsel and Vrijkotte2010; Henrichs et al., Reference Henrichs, Schenk, Roza, Van Den Berg, Schmidt, Steegers and Tiemeier2010; Hermon, Wainstock, Sheiner, Golan, & Walfisch, Reference Hermon, Wainstock, Sheiner, Golan and Walfisch2019; Heun-Johnson et al., Reference Heun-Johnson, Seabury, Menchine, Claudius, Axeen and Lakshmanan2019; Ibanez et al., Reference Ibanez, Charles, Forhan, Magnin, Thiebaugeorges, Kaminski and Saurel-Cubizolles2012; Katon, Russo, Melville, Katon, & Gavin, Reference Katon, Russo, Melville, Katon and Gavin2012; Khanghah, Khalesi, & Rad, Reference Khanghah, Khalesi and Rad2020; Kim et al., Reference Kim, Sockol, Sammel, Kelly, Moseley and Epperson2013; Kurki, Hiilesmaa, Raitasalo, Mattila, & Ylikorkala, Reference Kurki, Hiilesmaa, Raitasalo, Mattila and Ylikorkala2000; Lutsiv et al., Reference Lutsiv, McKinney, Foster, Taylor, Pullenayegum and McDonald2015; Mogos et al., Reference Mogos, Jones, Robinson, Whitehead, Piscotty and Goba2019; Navaratne, Foo, & Kumar, Reference Navaratne, Foo and Kumar2016; Packer, Pilliod, Chatroux, Caughey, & Valent, Reference Packer, Pilliod, Chatroux, Caughey and Valent2019; Palmsten, Setoguchi, Margulis, Patrick, & Hernández-Díaz, Reference Palmsten, Setoguchi, Margulis, Patrick and Hernández-Díaz2012; Qiu, Sanchez, Lam, Garcia, & Williams, Reference Qiu, Sanchez, Lam, Garcia and Williams2007; Ruiz et al., Reference Ruiz, Marti, Pickler, Murphey, Wommack and Brown2012; Schmidt et al., Reference Schmidt, Voorhorst, Van De Gaar, Keukens, Potter Van Loon, Snoek and Honig2019; Suri et al., Reference Suri, Altshuler, Hellemann, Burt, Aquino and Mintz2007; Venkatesh, Ferguson, Smith, Cantonwine, & McElrath, Reference Venkatesh, Ferguson, Smith, Cantonwine and McElrath2019; Yedid Sion, Harlev, Weintraub, Sergienko, & Sheiner, Reference Yedid Sion, Harlev, Weintraub, Sergienko and Sheiner2016; Yonkers, Gilstad-Hayden, Forray, & Lipkind, Reference Yonkers, Gilstad-Hayden, Forray and Lipkind2017), 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, Reference Avraham, Tamar, Eyal and Gali2020; Bánhidy, Ács, Puhó, & Czeizel, Reference Bánhidy, Ács, Puhó and Czeizel2006; Catov, Abatemarco, Markovic, & Roberts, Reference Catov, Abatemarco, Markovic and Roberts2010; Chen, Lin, & Lee, Reference Chen, Lin and Lee2010; De Vera & Bérard, Reference De Vera and Bérard2012; Garza-Veloz et al., Reference Garza-Veloz, Castruita-De La Rosa, Ortiz-Castro, Flores-Morales, Castañeda-Lopez, Cardenas-Vargas and Martinez-Fierro2017; Ibanez et al., Reference Ibanez, Charles, Forhan, Magnin, Thiebaugeorges, Kaminski and Saurel-Cubizolles2012; Kordi, Vahed, Rezaee, Reza, & Lotfalizadeh, Reference Kordi, Vahed, Rezaee, Reza and Lotfalizadeh2017; Pavlov, Steiner, Kessous, Weintraub, & Sheiner, Reference Pavlov, Steiner, Kessous, Weintraub and Sheiner2014; Ravid et al., Reference Ravid, Salzer, Arnon, Eisner, Wiznitzer, Weller and Hadar2018) also indicated an increased risk of HDP (RR = 1.49; 95% CI 1.13–21.98; 10 studies).
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., Reference Avalos, Chen and Li2015; Bandoli & Chambers, Reference Bandoli and Chambers2017; Catov et al., Reference Catov, Abatemarco, Markovic and Roberts2010; Cripe et al., Reference Cripe, Frederick, Qiu and Williams2011; De Vera & Bérard, Reference De Vera and Bérard2012; Garza-Veloz et al., Reference Garza-Veloz, Castruita-De La Rosa, Ortiz-Castro, Flores-Morales, Castañeda-Lopez, Cardenas-Vargas and Martinez-Fierro2017; Goedhart et al., Reference Goedhart, Snijders, Hesselink, Van Poppel, Bonsel and Vrijkotte2010; Henrichs et al., Reference Henrichs, Schenk, Roza, Van Den Berg, Schmidt, Steegers and Tiemeier2010; Ibanez et al., Reference Ibanez, Charles, Forhan, Magnin, Thiebaugeorges, Kaminski and Saurel-Cubizolles2012; Kim et al., Reference Kim, Sockol, Sammel, Kelly, Moseley and Epperson2013; Kurki et al., Reference Kurki, Hiilesmaa, Raitasalo, Mattila and Ylikorkala2000; Lang et al., Reference Lang, Zhang, Meng, Du, Cui and Li2019; Lutsiv et al., Reference Lutsiv, McKinney, Foster, Taylor, Pullenayegum and McDonald2015; Palmsten et al., Reference Palmsten, Setoguchi, Margulis, Patrick and Hernández-Díaz2012; Suri et al., Reference Suri, Altshuler, Hellemann, Burt, Aquino and Mintz2007; Suzuki, Shinmura, & Kato, Reference Suzuki, Shinmura and Kato2015; Winkel et al., Reference Winkel, Einsle, Pieper, Höfler, Wittchen and Martini2015) in order to determine if depression or anxiety preceded 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 = 1.27; 95% CI 1.07–1.50).Footnote 3
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 of HDP in women who received a diagnosis or self-reported clinically significant symptoms of depression and/or anxiety in pregnancy. 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.
Table 2. Summary of results of stratified meta-analyses
NOS, The Newcastle-Ottawa Scale; RR, relative risk; HDP, hypertensive disorders of pregnancy.
Heterogeneity
There was significant heterogeneity in the included studies, as indicated by an I 2 value of 97.0% on the full sample. When depression or anxiety were measured in early pregnancy, heterogeneity 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 construct such as depression (I 2 = 88.4%, p < 0.001) or anxiety (I 2 = 72.4%, p < 0.001) also show lowered heterogeneity values.
Publication bias
A funnel plot showed slight asymmetry, but overall did not suggest 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 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, 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.
Discussion
The primary aim of this systematic review and meta-analysis was to synthesize literature showing associations between depression and/or anxiety with HDP. Three main findings were observed. First, in the overall meta-analysis of over 61.2 million pregnancies across 44 studies, women with clinically elevated symptoms or a diagnosis of depression and/or anxiety during pregnancy had an increased RR of 39% for diagnosis of an HDP compared to the non-exposed group. Second, subgroup analysis examining associations between depression and anxiety assessed prior to 20 weeks of gestation and diagnosis of HDP also showed an association, 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 depression or anxiety early in pregnancy (<20 weeks), prior to the diagnosis 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, Reference Hamilton and Gotlib2008). 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 focusing on anxiety as opposed to those focused on depression. Although there is some evidence linking physiological mechanisms of hypertension to anxiety specifically (for a review, see Johnson, Reference Johnson2019), there is also strong evidence that both anxiety and depression have common and unique contributions to measurements of cardiovascular health (Firulescu, May, Ferrer, Fincham, & Sanchez-Gonzalez, Reference Firulescu, May, Ferrer, Fincham and Sanchez-Gonzalez2017). 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., Reference Moffitt, Harrington, Caspi, Kim-Cohen, Goldberg, Gregory and Poulton2007). 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, Fischer, Heuszer, Geiger, & Schmieder, Reference Schobel, Fischer, Heuszer, Geiger and Schmieder1996). During pregnancy, the cardiovascular system undergoes prominent changes as blood pressure and heart rate adjust to accommodate fetal growth (Grindheim, Estensen, Langesaeter, Rosseland, & Toska, Reference Grindheim, Estensen, Langesaeter, Rosseland and Toska2012; Mastrobattista & Monga, Reference Mastrobattista, Monga, Resnik, Lockwood, Moore, Greene, Copel and Silver2018), and the sympathetic nervous system has been identified as a possible mediator between stress and cardiovascular disease (Hering, Lachowska, & Schlaich, Reference Hering, Lachowska and Schlaich2015). Furthermore, depression or anxiety in pregnancy may also cause physiological changes responsible for hypertensive outcomes through shared physiological mechanisms between mood and blood pressure regulation (Sandman, Wadhwa, Chicz-DeMet, Dunkel-Schetter, & Porto, Reference Sandman, Wadhwa, Chicz-DeMet, Dunkel-Schetter and Porto1997). Finally, behavioral risk factors associated with depression and anxiety, including lowered physical activity (Schuch et al., Reference Schuch, Vancampfort, Firth, Rosenbaum, Ward, Reichert and Stubbs2017), increased substance use (Lai, Cleary, Sitharthan, & Hunt, Reference Lai, Cleary, Sitharthan and Hunt2015), and poor sleep (Tomfohr, Buliga, Letourneau, Campbell, & Giesbrecht, Reference Tomfohr, Buliga, Letourneau, Campbell and Giesbrecht2015), 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 hypertension. 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 emerging area, and there is increasing evidence that there may be a cumulative impact of depression and/or anxiety on negative obstetrical 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 hypertension alone (Hilmert et al., Reference Hilmert, Schetter, Dominguez, Abdou, Hobel, Glynn and Sandman2008; Horsley et al., Reference Horsley, Tomfohr-Madsen, Ditto and Tough2019). 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., Reference Curry, Krist, Owens, Barry, Caughey, Davidson and Wong2019; Marchesi et al., Reference Marchesi, Ossola, Amerio, Daniel, Tonna and De Panfilis2016). Guidelines endorsed by numerous countries now recommend screening and treatment for depression and anxiety during the perinatal period (Austin & Highet, Reference Austin and Highet2017; Williams, Reference Williams2014). 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 literature 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 previous 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 criteria for depression and anxiety is a strength of the current analysis, providing a foundation for identifying evidence-based interventions that can reduce or prevent the experience of the psychological 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 findings (Hartling et al., Reference Hartling, Featherstone, Nuspl, Shave, Dryden and Vandermeer2017). Furthermore, diagnostic criteria surrounding 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, Reference Whelton and Carey2017). This could change the number of women diagnosed with pre-existing hypertension and alter the overall prevalence of hypertensive disorders in pregnancy 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 confirm 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 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 cardiovascular 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 indication 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, Reference Bayrampour, Tomfohr and Tough2016), 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 relationship 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 depression, anxiety, and HDP. The HDP outcomes reported varied by study and these variations represent important clinical distinctions in the severity of HDP. Pre-eclampsia generally represents the more severe condition, with stronger associations with maternal morbidity and mortality than gestational hypertension alone (Say et al., Reference Say, Chou, Gemmill, Tunçalp, Moller, Daniels and Alkema2014). 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 depression 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, Reference Milgrom and Gemmill2014).
In addition to measurement variation, there are other possible sources of heterogeneity including geographic location and race/ethnicity of participants. Included studies were conducted 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 ethnicity. 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, Reference Shen, Tymkow, Macmullen and Utcomes2005; Zhang et al., Reference Zhang, Ding, Liu, Chen, Wu, Zhang and Yu2013).
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 variations 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 demonstrated 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., Reference Regitz-Zagrosek, Blomstrom Lundqvist, Borghi, Cifkova, Ferreira, Foidart and Warnes2011; Umesawa & Kobashi, Reference Umesawa and Kobashi2017). 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.
