key: cord-309892-z7rb7adi
authors: TRAYLOR, Claire S.; JOHNSON, Jasmine; Kimmel, Mary C.; MANUCK, Tracy A.
title: Effects of psychological stress on adverse pregnancy outcomes and non-pharmacologic approaches for reduction: an expert review
date: 2020-09-24
journal: Am J Obstet Gynecol MFM
DOI: 10.1016/j.ajogmf.2020.100229
sha: 
doc_id: 309892
cord_uid: z7rb7adi

Both acute and chronic stress can cause allostatic overload, or long-term imbalance in mediators of homeostasis, that results in disruptions in the maternal-placental-fetal endocrine and immune system responses. During pregnancy, disruptions in homeostasis may increase the likelihood of preterm birth and pre-eclampsia. Expectant mothers traditionally have high rates of anxiety and depressive disorders and many are susceptible to a variety of stressors during pregnancy. These common life stressors include financial concerns and relationship challenges and may be exacerbated by the biologic, social and psychologic changes occurring during pregnancy. In addition, external stressors such as major weather events (e.g., hurricanes, tornados, floods) and other global phenomena (e.g., the COVID-19 pandemic) may contribute to significant stress during pregnancy. This review investigates recent literature published about the use of non-pharmacologic modalities for stress relief in pregnancy and examines the interplay between psychiatric diagnoses and stressors, with the purpose of evaluating the feasibility of implementing non-pharmacologic interventions as sole therapies or in conjunction with psychotherapy or psychiatric medication therapy. Further, the effectiveness of each non-pharamacologic therapy in reducing symptoms of maternal stress is reviewed. Mindfulness meditation and biofeedback have shown effectiveness in improving one’s mental health such as depressive symptoms and anxiety. Exercise, including yoga, may improve both depressive symptoms and birth outcomes. Expressive writing has successfully been applied post-partum and in response to pregnancy challenges. Though some of these non-pharmacologic interventions can be convenient and low cost, there is a trend towards inconsistent implementation of these modalities. Future investigations should focus on methods to increase ease of uptake , ensure each option is available at home, and a standardized way to evaluate whether combinations of different interventions may provide added benefit.

Both acute and chronic stress can cause allostatic overload, or long-term imbalance in 23 mediators of homeostasis, that results in disruptions in the maternal-placental-fetal endocrine 24

and immune system responses. During pregnancy, disruptions in homeostasis may increase the 25 likelihood of preterm birth and pre-eclampsia. Expectant mothers traditionally have high rates of 26 anxiety and depressive disorders and many are susceptible to a variety of stressors during 27 pregnancy. These common life stressors include financial concerns and relationship challenges 28 and may be exacerbated by the biologic, social and psychologic changes occurring during 29

pregnancy. In addition, external stressors such as major weather events (e.g., hurricanes, 30 tornados, floods) and other global phenomena (e.g., the COVID-19 pandemic) may contribute to 31 significant stress during pregnancy. 32

This review investigates recent literature published about the use of non-pharmacologic 33 modalities for stress relief in pregnancy and examines the interplay between psychiatric 34 diagnoses and stressors, with the purpose of evaluating the feasibility of implementing non-35 pharmacologic interventions as sole therapies or in conjunction with psychotherapy or 36 psychiatric medication therapy. Further, the effectiveness of each non-pharamacologic therapy 37 in reducing symptoms of maternal stress is reviewed. Mindfulness meditation and biofeedback 38 have shown effectiveness in improving one's mental health such as depressive symptoms and 39 anxiety. Exercise, including yoga, may improve both depressive symptoms and birth outcomes. 40

Expressive writing has successfully been applied post-partum and in response to pregnancy 41 challenges. Though some of these non-pharmacologic interventions can be convenient and low 42 cost, there is a trend towards inconsistent implementation of these modalities. Future 43 investigations should focus on methods to increase ease of uptake , ensure each option is 44

Stress is a frequently used, ambiguous term. 1 The 'allostatic model' has been developed to 48 help clarify these ambiguities and explain the effects of acute versus chronic stress responses. 2 49 Initial conceptions of stress response were centered around homeostasis, a concept referring to 50 self-regulating processes that maintain the stability of an individual's essential systems. Cohen 51 et al. provide a working definition of stress as "when environmental demands tax or exceed the 52 adaptive capacity of an organism, resulting in psychological and biological changes that may 53 place persons at risk for disease." 3 These environmental demands may be internal, relating to 54 an individual's disposition, or external, relating to an individual's life circumstances. Acute stress 55 is an intense, but relatively short-lived response to stressors whereas chronic stress is the result 56 of unresolved stressors that are experienced for a longer period of time. 57

Repeated or chronic stress contributes to the cumulative allostatic load-the "wear and tear 58 on the body," or a sum of the lifetime stress exposure. 4,5 Allostatic load increases over time and 59 represents physiologic consequences of heightened neural or neuroendocrine responses. 6 60 Hypothalamic-pituitary-adrenal (HPA) axis hormones -including cortisol, catecholamines such 61 as epinephrine, and cytokines -are all primary mediators impacting allostasis. 2 When these 62 primary mediators go beyond the limits of homeostatic mechanisms and become unbalanced, 63 the body is only able to sustain this state without negative effects for a limited time. 2 A 64 prolonged imbalance of these primary homeostatic mediators results in allostatic overload. 65

Additionally, chronic stressors or repeated acute stressors may result in changes related to 66 glucocorticoid genes, by alterations of the epigenome and/or transcriptome, and hasten 67 disease. However, though the initial stressful insult cannot always be prevented, epigenetic and 68 transcriptomic effects are dynamic, and potentially reversible through treatment. 7-12 69

Stress is common among pregnant women. In 2009-2010, data from the US-wide Centers 71

for Disease Control Pregnancy Risk Assessment Monitoring System found that nearly 75% of 72 J o u r n a l P r e -p r o o f postpartum mothers reported at least one major stressful event in the year leading up to delivery 73 of their baby. 13 The most commonly cited stressors experienced during pregnancy included 74 moving to a new address, arguing with a partner more than usual, serious illness and 75 hospitalization of a family member, and inability to pay bills. In addition, external stressors such 76 as extreme weather events (e.g., hurricanes, tornados, floods) and other global adverse events 77 (e.g., the COVID-19 pandemic) may contribute to significant acute and chronic stress during 78 pregnancy. Reports of perceived stress varied widely by race and ethnicity, with non-Hispanic 79

American Indian/Alaska Native women reporting highest levels of stress and non-Hispanic 80

Asian women reporting the lowest. 13 81

Chronic stress may be associated with adverse pregnancy outcomes via a positive feedback 83 loop. Maternal-placental-fetal neuroendocrine interaction and immune responses are stress-84 sensitive, and thus may affect birth outcomes. Maternal stress is associated with cortisol 85 release. 14,15 High cortisol levels reduce lymphocyte sensitivity to glucocorticoids by binding to 86 glucocorticoid receptors; subsequently, as steroid resistance is developed, there is an increased 87 release of pro-inflammatory cytokines. 15 Furthermore, maternal stress influences circulating 88 levels of inflammatory markers by increasing pro-inflammatory cytokines interleukin-1β, 89 interleukin-6, and tumor necrosis factor α, and decreasing anti-inflammatory cytokine 90 interleukin-10. 14 These inflammatory markers dampen the immune system response, increasing 91 the susceptibility to adverse pregnancy outcomes, such as PTB. 14 Women who develop adverse 92 pregnancy complications requiring early delivery or resulting in other maternal or neonatal 93 morbidities may then experience additional stress, furthering the loop. 94

Previous studies have found that minority and low-income pregnant women may have 95 higher baseline levels of cortisol compared to women of other situations, supporting the 96 association between chronic stress, increased allostatic load, and higher rates of adverse 97 pregnancy outcomes among these high risk obstetric populations. 16 One stressor of particular 98 J o u r n a l P r e -p r o o f concern to pregnant women of color in the US is racism. Racism (and/or discrimination) is 99 typically defined as differential treatment based on ones' skin color or racial identity. Racism 100 affects over 68% non-Hispanic black women in the U.S. It is hypothesized that racism may be a 101 significant contributor to the disparities in adverse birth outcomes (e.g., PTB and preeclampsia) 102 among non-Hispanic black women compared to non-Hispanic white women. 15 The chronic 103 stress associated with racism contributes to an increased allostatic load and a more rapid 104 decline in health during an individual's lifetime-it is a major contributing factor to the 105 'weathering hypothesis.' Weathering is the premature aging of the body due to endurance of 106 adverse events -this can be both physically and psychological. This hypothesis is supported by 107 studies suggesting that age-related increases in preterm birth are higher among non-Hispanic 108 black women compared to non-Hispanic white women 17 and that racial and ethnic disparities in 109 PTB and other adverse pregnancy outcomes persist among women of high socioeconomic 110 status. 18 111

Acute stress, chronic stress, and allostatic overload have all been associated with a variety 113 of adverse pregnancy outcomes, including spontaneous PTB, preeclampsia, neonatal morbidity, 114 and low birth weight (Table 1) . 14, 15, 19 In turn, PTB (regardless of indication) is associated with a 115 higher risk of short-term neonatal morbidities (including neurologic, pulmonary, cardiovascular, 116 gastrointestinal, immune and metabolic complications) and long-term complications among 117 survivors (e.g., cerebral palsy, neurodevelopmental delay, visions problems, and hearing 118 loss). 20-26 As the total allostatic load increases, the likelihood of adverse pregnancy outcomes 119 may also increase ( Figure 1) . 120

Natural disasters and adverse national and international events (e.g., pandemics) provide a 121 unique opportunity to study the effects of a 'universally stressful' exposure on pregnancy 122 outcomes. While it can be difficult to navigate ethical considerations of human research 123

involving an imposed stress variable, populations and individuals intrinsically experience varying 124 J o u r n a l P r e -p r o o f levels of impact, and thus stress exposure, in the event of a population-wide stressor. These 125 stressful experiences -including destructive weather events (e.g., hurricanes, earthquakes) and 126 more chronic population-wide stressors (e.g., local political unrest, war, pandemics) may also 127 activate both the acute and chronic stress response feedback loops in pregnant individuals. 128

Depression and anxiety during pregnancy is very common. One in five women will have an 130 anxiety disorder in pregnancy, 27 and 10-14% of women in the general obstetric population meet 131 criteria for major depression during pregnancy. 28 However, anxiety and depressive symptoms 132 are as high as 25-50% in pregnancy, when symptoms are present but insufficient to meet full 133 diagnostic criteria for a specific anxiety or depressive disorder. 29-31 In a study of pregnant low-134

income Black women engaging in home-visiting programs in an urban environment, over 20% 135 met full criteria for Major Depressive Disorder in pregnancy, 31 further supporting that non-136

Hispanic black women who face higher stress also have higher rates of depression. 137

Women with a previous diagnosis of depression or anxiety prior to pregnancy, past 138 pregnancy or delivery complications including pregnancy loss and stillbirth, history of adverse 139 life events (e.g., abuse), and particularly those with multiple traumatic events have a higher 140 allostatic load and higher rates of antenatal depression and anxiety. 32 Similar to biologic findings 141 seen in those with chronic stress, women with Major Depressive Disorder during pregnancy 142 have increased pro-inflammatory cytokines and a blunted cortisol awakening response. 33 143

Further, prenatal anxiety is associated with increased cortisol levels and pro-inflammatory 144 cytokines. 34 Women with both severe depression and severe anxiety during the third trimester 145 had higher levels of IL-6, IL-2, IL-9 and IL-17A. 35 146 147

Though many pregnant women are exposed to both acute and chronic stressors, not all 149 women who are exposed have adverse pregnancy outcomes. This may explain, in part, why 150 J o u r n a l P r e -p r o o f pregnancy outcomes remain variable in the setting of more widespread adverse events. The 151

sum of an individual's prior social experiences (both positive and negative), and their reaction to 152 these experiences influence whether exposure to new acute or chronic stressors disrupts 153 homeostasis and results in disease or adverse outcomes. Hogue and colleagues positioned 154 racial discrimination and spontaneous PTB within a stress and coping framework whereby 155 effective coping may reduce the negative impact of the stress of discrimination, but ineffective 156 coping may allow the stress to cause a disruption in homeostasis and contribute to adverse birth 157 outcomes. 36 Others report that though women have elevated risk of spontaneous PTB when 158 reporting lifetime racism (OR 1.5, 95% CI 0.9-2.8) and racism in the past year (OR 2.5, 95%1.2-159 5.2), this risk can be abrogated by "active coping." 37 Finally, though one study of 3,021 women 160 in Canada found that stress was a significant risk factor for PTB (OR 1.73, 95% CI 1.07-2.81), 161 the risk of prematurity was highest among those with low levels of social support or optimism. 38 162

Based on these data, the successful reduction on the biological effects of stress during 163 pregnancy has the potential for profound impacts on maternal health and pregnancy outcomes 164 for certain populations. Though pharmacologic therapy including selective serotonin reuptake 165 inhibitors (SSRIs) and benzodiazepines have a role in treating depression or anxiety in 166 pregnancy, pharmacologic treatments for the different alterations in stress responses that have 167 built up over time are more elusive, and the effect on pregnancy outcomes remains under-168 investigated. Of concern, benzodiazepine use in combination with SSRI therapy has been 169 associated with worse adverse behavioral effects in the infants. 39 Furthermore, though rates of 170 depression are high, only 8.6% receive adequate treatment in pregnancy, and data regarding 171 remission rates of depression with medication during pregnancy are limited. 40 Finally, women may be taking appropriate doses of pharmacotherapy but need or desire 186 an additional adjunct therapy. Psychotherapy also has a role in the treatment of stress during 187 pregnancy through cognitive behavioral therapy and other approaches, but is excluded from this 188 review because access to psychotherapy may be limited due to provider availability or financial 189 concerns. Therefore, the objective here is to review the available use of low-cost, logistically 190 feasible, non-pharmacologic therapies to reduce stress during pregnancy (Figure 2 ), and to 191 discuss future avenues for research and clinical care in this area. 192 Section 2: Interventions to reduce stress during pregnancy 193

Meditation is a mental exercise that improves attention and emotional self-regulation. 195

Some types of meditation include mindfulness, breathing, mantra recitation, and visualizations. 46 196 Grounded in Buddhist origins, mindfulness is described as attention to and awareness of 197 present perceptions. 47 It is a form of experiential processing in which instances are observed 198 from a wider perspective that recognizes influential judgements and associations. 45 In contrast, 199 during conceptual processing, an individual evaluates situations within the context of self-200 concern. In recent literature, mindfulness has been of prominent interest as a potential 201 J o u r n a l P r e -p r o o f therapeutic tool because it is low cost and only requires a relatively short investment of time 202 each day. An integrative review of mindfulness in the workplace reported improvements in 203 attention, cognitive capacity, emotional reactivity, self-regulation, and stress response. 48 As a 204 targeted intervention for stress, mindfulness has shown effectiveness in reducing negative 205 outcomes such as anxiety, depression, and chronic pain. 46 206

In pregnancy, mindfulness has potential as a therapy to reduce stress and improve birth 207 In a randomized controlled trial of non-pregnant students with chronic, pain, and anxiety, 228 mindful breathing facilitated by a 12-minute smartphone-based task is proposed to decrease 229 HRV. 52 Similarly, HRV biofeedback is a non-invasive technique that utilizes metronomic 230 breathing while monitoring one's parasympathetic activity to improve HRV measures. 43 HRV 231 biofeedback has been shown to improve control in response to negative situations, 43 and has 232 been associated with reductions in self-reported perceived stress and anxiety. 53 Two studies of 233 perinatal women, one including women with threatened preterm labor and the other including 234 women in the early postpartum period utilized HRV biofeedback versus control groups. [54] [55] [56] In 235 the study of antenatal women with threatened preterm labor, 48 women were randomized to 236 HRV biofeedback vs. standard care at an average 29 weeks' gestation; those randomized to 237 HRV biofeedback had a decrease in their perception of chronic stress during the study period, 238 and the rate of PTB was lower than in the control group (13% vs. 33%; p value=not significant, 239 exact value not provided in manuscript). 55 In the early postpartum study, use of HRV 240 biofeedback was associated with significant improvements in HRV measures and in scores on 241 the Edinburgh Postnatal Depression Scale compared to those who did not use HRV feedback. 54 242

in anxiety symptoms and improvement in psychological well-being. 57 Taken together, these 244 data suggest that biofeedback -particularly when linked to HRV monitoring -may be a method 245 of determining who is responding physiologically to mindfulness and deep breathing practices. 246

Studies have already shown efficacy in reducing perceived stress and anxiety during 247 pregnancy, including among pregnant women with threatened preterm labor. 248

According to the National Center for Health Statistics, over 35 million American adults 250 actively practiced yoga in 2017, and this number is still growing. 58 Yoga is the most commonly 251 used complementary health approach in the U.S. and consists of three aspects: physical 252 postures (asanas), breathing techniques (pranayama), and meditation (dhyana). 58 Originating 253 from India as a spiritual practice, yoga has grown and evolved into many different styles such as 254

Hatha, Iyengar, Bikram, and integrated approaches. 59 While Hatha yoga is the most popular 255 form, these different styles do not significantly differ in the probability of reaching positive 256 conclusions in recent research (p=0.191). 59 257

Yoga is a popular non-pharmacologic intervention available to pregnant women that may 258 improve both birth outcomes and mental health. Prenatal yoga classes are commonly available 259 across the United States. In addition, yoga instruction specifically tailored for pregnant women is 260 available for 'free' online through smartphone apps and on publicly available websites. In a 261 study investigating the effects of prenatal yoga on birth outcomes, 84 women with depressive 262 symptoms were randomized to yoga, massage therapy, or standard prenatal care from 20 to 32 263 weeks' gestation. A greater improvement in depression scores, decreased anxiety scores, 264 decreased anger scores, decreased back and leg pain scores, and increased relationship 265 scores were seen for those in both the yoga group and the massage therapy group, but not the 266 control group. In addition, those in the yoga and massage group delivered later (mean 38.6 and 267 38.4 weeks', respectively) than those in the control group (mean 36.7 weeks' gestation). 60 A 268

Taiwanese study evaluating the effects of prenatal yoga on stress and immune function 269 intervention. However, it is it important to note that the trials evaluated in both analyses were 289

typically preliminary with small sample sizes. 290

As defined by the American College of Sports Medicine, exercise is "a type of physical 292 activity consisting of planned, structured, and repetitive bodily movement" that is produced by 293 skeletal muscle contraction and leads to increased energy expenditure. 65 Exercise is known to 294 help prevent and treat metabolic or cardiovascular diseases; it has also been shown to reduce 295 depressive symptoms. 65 The American College of Obstetrics and Gynecology recommends 296 women with uncomplicated pregnancies should complete moderate-intensity physical activity for 297 at least 20-30 minutes on most or all days of the week. 66 Historically, intense exercise has been 298 assumed to have negative consequences for mother and child. 66 In fact, women tend to reduce 299 their physical activity during pregnancy and less than half of pregnant women meet exercise 300 recommendations. 61 While there may be a theoretic concern regarding vigorous exercise in 301 some situations (e.g., women with premature cervical dilation or threatened preterm labor), 302 there is minimal evidence to suggest harm, and one observational study of women with short 303 cervix suggested a higher risk of preterm birth among women with activity restrictions compared 304 J o u r n a l P r e -p r o o f to those without such restrictions. 67 An analysis of exercise and pregnancy loss referencing 6 305 cohort studies and reviews including over 120,000 women found that regular exercise for up to 306 7 hours a week, including low-and high-intensity activity, is not associated with increased rates 307 of miscarriage. 68 308

The benefits of exercise during pregnancy span both physical and mental capacities. A 309 systematic review and meta-analysis of low-impact physical activity in pregnancy evaluated 30 310 randomized-controlled trials and 51 cohort studies for maternal-child health outcomes. 69 Regular 311 exercise was associated with lower weight gain during pregnancy, a lower likelihood of 312 gestational diabetes mellitus, and a lower risk of preterm delivery. Less is understood about the 313 relationship between stress and exercise in pregnancy. However, there is a direct association 314 between low exercise frequency and higher reports of stress-related symptoms. 70,71 One 315 randomized controlled trial of 167 women explored depression reduction and exercise during 316 pregnancy. 72 Women randomized to the exercise group completed three 60-min sessions of 317 supervised physical activity per week throughout pregnancy. Compared to the control group, 318 women in the exercise intervention group scored significantly lower on the Center for 319

Epidemiologic Studies Depression Scale (7.76 ± 6.30 vs. 11.34 ± 9.74, p = .005) at the end of 320 the study. 72 321

Expressive writing involves a personal and often emotional reflection of thoughts or memories; it 323 focuses on detailing one's feelings while writing with the purpose of potentially easing emotional 324 trauma. It was developed as a type of therapy by James W. Pennebaker in the late 1980s after 325 his research found that writing for 15 minutes a day for at least 3 consecutive days about 326 previous distressing experiences was associated with significantly fewer visits to a physician in 327 the following months. 73 Subsequently, various medical disciplines have started using expressive 328 writing; it is an attractive therapeutic option as it is accessible, customizable, does not require 329 significant time commitment, and is low cost. Additionally, it may be more convenient compared 330 with traditional psychotherapy given the lack of mental health professionals in many areas, 331 though it may also be effective if the pregnant woman is able to share some of her writing with a 332 health care professional. Although a quantitative survey of pregnant women found that women 333 preferred video telehealth therapy compared to computer-assisted therapy and self-guided 334 online therapy, 74 psychotherapy access is limited for many individuals due to lack of providers 335 and other barriers including financial and scheduling logistics. Pregnant women rated 336 computer-based support as acceptable, 74 Meditation and mindfulness, biofeedback, yoga, exercise, and expressive writing have 361 not been explored as possible stress therapy options until recent years. Therefore, research 362 conducted on these interventions is largely preliminary and prospective. Support for these 363 interventions, particularly expressive writing, could benefit from more randomized, controlled 364 trials with larger sample sizes. Likely there may be characteristics that make some women more 365 responsive to on over another (e.g., anxious depression versus non-anxious depression). In 366 addition, combining some of these might also lead to greater results, e.g., a mindfulness 367 practice that also includes expressive writing. 368

Non-pharmacologic interventions -including, but not limited to those discussed here -369 have the potential to be affordable and widely available. Additionally, with the rising popularity of 370 online classes and support groups, all of the above interventions can be completed at-home. 371

This holds great potential for times when leaving one's home is not possible-a period where 372 situational stress can even be elevated. For example, the methods for stress reduction outlined 373 here provide a safe and potentially effective way for women to reduce stress during pregnancy 374 during a pandemic. Non-pharmacologic interventions also provide patients with a choice of 375 preference; patient autonomy will likely improve participation and engagement. Expressive 376 writing, mindful meditation, biofeedback, yoga, and exercise provide a broad range of options in 377 terms of metacognition and physicality. Finally, these interventions are novel strategies that may 378 be readily available to women of all social and racial / ethnic backgrounds, and the benefits of 379 such could help to close the health disparities gap with respect to maternal and fetal health 380 outcomes. These may also augment pharmacologic treatment of depression and anxiety just as 381 therapy and pharmacotherapy combined can be most effective for those with severe depression 382 or anxiety. 81,82 383

Thus, non-pharmacologic interventions for stress reduction provide a viable option 384 available to women during pregnancy. Nevertheless, improvements in the implementation of 385 these options should be explored. Providers must also take into consideration the unique 386 situation and variable social determinants of health that may make some stress reducing 387 modalities difficult to routinely practice -such as one's work schedule, caregiver needs, unstable 388 housing and/or internet access, etc. In one study, the viability of using expressive writing was 389 studied through agreement of participation and completion of full intervention. Around 8,000 390 eligible women were contacted, approximately 1,400 replied to the study invitation, and 854 391 agreed to participate. 83 However, by the 6-month follow-up, only 290 women remained. 68 392

Additionally, less than 30% of the women in both writing groups fulfilled the intervention 393 conditions completely. 83 Most of the women who did not choose to participate marked "too busy" 394 as the reason for their decline. These results reveal that although expressive writing is 395 theoretically more convenient than other interventions, many patients struggled to complete the 396 intervention conditions to the full extent. Horsch's study supports this idea as although 94 of the 397 105 eligible mothers contacted agreed to participate, only 54 completed the study through to the 398 3-month follow-up. 84 Further, it is unknown whether combinations of these approaches -e.g., 399 expressive writing and yoga or exercise -might improve pregnancy outcomes. Finally, 400

incentivizing the use effective non-pharmacologic therapies for providers could also help with 401 update of the modalities discussed in this review. In the future, ways to incentivize completion 402 and emphasize the potential importance of writing therapy and meditation should be researched 403 for all stakeholders. 404

Expressive writing, meditation, mindfulness, biofeedback, yoga, and exercise are effective 406 therapies for emotional and physical health. While these methods have not always been 407 considered for medical treatment of individuals, new research is continually revealing the 408 potential of these interventions to improve health outcomes. For example, other non-409 pharmacologic approaches to reduce stress in pregnancy -including music therapy and a 410 smartphone app specifically designed to reduce stress in pregnancy -have also been 411 evaluated, but more data are needed to determine the effectiveness of these additional 412 modalities. 85, 86 The application of these accessible and widely available interventions to reduce 413 stress during pregnancy. In turn, by limiting the negative implications associated with stress in 414 pregnancy, these non-pharmacologic options could help improve birth outcomes. Research 415 should continue to expand on the strengths of each intervention as effective, affordable, 416 adaptable to make them a more convenient option for stress alleviation in addition to research 417 on how these non-pharmacologic methods could further enhance the effects of pharmacologic 418 therapies to treat psychiatric conditions. 419 

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