Trauma and Posttraumatic Stress Disorder as Important Risk Factors for Gestational Metabolic Dysfunction

Keywords

trauma - PTSD - stress - metabolic disorders during pregnancy - gestational diabetes mellitus - hypertensive disorders of pregnancy - fetal growth restriction

Metabolic disorders during pregnancy, which include gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), and fetal growth restriction (FGR), are adverse health outcomes that jeopardize the wellbeing of both pregnant persons and their offspring during and beyond gestation. During gestation, physiological adaptations across multiple tissue and organ systems occur in unison to meet the energy demands of the growing fetus.[1] These adaptations create a metabolic challenge that increases risk for gestational metabolic disorders. Increased risk for gestational metabolic dysfunction is reflected in the prevalence of prenatal metabolic disorders, with baseline rates in the United States for GDM ranging from 5 to 10% and HDP and FGR around 3 to 10%.[2] [3] [4] [5]

The burden of metabolic disorders during pregnancy is disproportionately distributed among racial-ethnic lines, as demonstrated by higher GDM rates among Asian and Hispanic/Latinx populations,[6] higher HDP rates among black and Hispanic/Latinx populations,[7] and higher FGR rates among black populations[1] [8] relative to white populations. Additionally, non-white pregnant persons have a higher risk for adverse outcomes when diagnosed with gestational metabolic disorders. Preeclampsia, a subset of HDP, is the second leading cause of maternal mortality[6]; the risk for severe morbidity is 9.8 and 7.7% in non-Hispanic black and Hispanic/Latinx pregnant persons respectively, compared with 6.1% morbidity risk in white pregnant persons.[9] Gestational hypertension (GHTN) prevalence shows similar racial-ethnic inequities, with non-Hispanic black and Hispanic/Latinx pregnant persons at higher risk for pregnancy-associated stroke than white pregnant persons and nonpregnant persons.[2] [3] Given the dangers of gestational metabolic dysfunction, it is essential to identify risk factors that alter metabolic physiology in pregnancy and understand how those risk factors contribute to racial-ethnic disparities in pregnancy-related health.

Risk factors for gestational metabolic disease include age, income, family history, preexisting metabolic disease like type 2 diabetes mellitus (T2DM), and high blood pressure.[4] [5] [6] [7] However, when controlling for these risk factors, pregnant persons of color, in particular black pregnant persons, still experience increased rates of gestational metabolic disease as compared with non-Hispanic white pregnant persons, indicating that psychosocial factors may modify gestational metabolic health as well.[8] Trauma exposure and resulting posttraumatic stress disorder (PTSD) are two psychosocial risk factors that may contribute to gestational metabolic dysfunction and associated racial-ethnic health disparities. Traumatic stress exposure leads to set of maladaptive physiological responses that adversely impact overall health, including behavioral health.[10] PTSD is a psychiatric disorder that occurs after exposure to a traumatic event and adversely impacts individuals' mood and fear responses.[9] Critically, non-white nonpregnant individuals, particularly black and Latinx/Hispanic individuals, are exposed to higher rates of traumatic events and suffer more from PTSD.[11] [12] [13] [14] This increased exposure to trauma and PTSD in non-white populations not only impacts mental health but may also adversely impact metabolic function. In particular, trauma exposure and PTSD are associated with increased risk for the development of T2DM,[13] hypertension[14] and cardiovascular disease in nonpregnant populations.[15] Exposure to trauma and PTSD negatively impact multiple biological systems, including the autonomic nervous system (ANS) and hypothalamic-pituitary adrenal axis (HPA) stress systems, whose dysregulation can lead to heightened systemic inflammation.[1] [15] [16] Dysregulation of these physiological systems maintains the body in a catabolic state of glucose production, predisposing individuals to increased risk of metabolic dysfunction.[16] [17] [18]

Despite the link between trauma, PTSD, and metabolic dysfunction in nonpregnant persons, it remains unclear how trauma and PTSD impact risk for metabolic dysfunction in pregnancy and associated pregnancy-related health disparities. Thus, in the current narrative review, we will summarize and synthesize significant findings to date that address the association between trauma and PTSD and gestational metabolic diseases including GDM, HDP, FGR, and low birth weight (LBW). To contextualize relevant findings, we first discuss underlying biological mechanisms by which trauma exposure and PTSD act as chronic stressors that lead to metabolic dysfunction in nonpregnant persons. Following, we assess and evaluate findings form the limited studies that address the relationship between metabolic dysfunction in pregnant persons and traumatic stress exposure and PTSD, while highlighting socioeconomic and racial-ethnic study demographics. Uncovering the biological mechanisms that underlie gestational metabolic risk is critical to developing preventive and interventional treatments for pregnant persons at high risk for gestational metabolic disease. Ultimately, understanding the role of trauma and PTSD in gestational metabolic dysfunction is a crucial component in better understanding the biological mechanisms that underlie racial-ethnic and socioeconomic pregnancy-related health disparities and associated infant health complications.

Biological Pathways Underlying Stress Effects on Metabolism Outside of the Context of Pregnancy

Overview of the Physiological Stress Response Systems

The stress response is a broad term that refers to any physiological change in response to a physical or psychological stimulus (stressor) that is perceived as a danger to an individual.[17] The stress response evolved to promote the survival of organisms and is composed of the co-activation of the fast-acting ANS, which activates the immune system to prepare for potential wounding, and the slower acting HPA axis. The ANS is divided into the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS), which work in a complimentary fashion alongside the HPA axis to regulate physiological and behavioral responses when danger is detected.[18] During exposure to an acute stressor, the SNS and HPA axis signal the release of epinephrine and cortisol from the adrenal glands, respectively. These hormones work in tandem to increase heart rate, respiration rate, and blood vessel dilation to increase the availability of oxygen to accommodate the body's perceived emergency state.[19] HPA axis-induced release of cortisol initiates catabolic processes in liver, fat, and muscle tissue via activation of glucocorticoid receptors, therefore increasing glucose availability that is critical for providing the body and brain with an adequate energy supply in the face of an acute stressor.[20]

The ANS and HPA axis also stimulate and inhibit inflammatory processes, respectively, in response to acute stress.[21] More specifically, these two stress systems work in tandem: epinephrine quickly stimulates the immune system to increase blood levels of inflammatory cytokines,[22] while slower acting cortisol-driven negative-feedback mechanisms of the HPA axis inhibit the ANS-driven inflammatory response, preventing inflammatory cytokines from damaging important organ systems.[22] [23] After the eminent threat of the acute stressor has subsided, both the ANS and HPA axis act to return homeostasis. Specifically, SNS activity is downregulated and that of the PSNS is upregulated.[24] Similarly, HPA-axis negative feedback inhibition of the HPA axis by glucocorticoids results in termination of the neuroendocrine stress response.[19] [25] While exposure to acute stressors initiates this short-term adaptive stress response, exposure to prolonged and repeated stressors dysregulates ANS, HPA axis, and inflammatory functions, leading to dysfunction of critical bodily processes, including metabolism.[10] As common and debilitating chronic stressors, repeated exposure to trauma (e.g., traumatic stressors) and resulting PTSD are important risk factors to consider in the context of metabolic dysfunction.

ANS Dysregulation and Adverse Impacts on Metabolic Function

Exposure to traumatic stressors leads to continuous hyperactivation of the SNS, which hinders the normal counteraction of the PSNS and disturbs ANS homeostasis ([Fig. 1A]).[26] Specific to metabolism, traumatic stress induces an increase in epinephrine and norepinephrine release by the ANS, leading to maintenance of high heart rate, blood pressure, and serum cortisol, as well as a reduction in heart rate variability (HRV), all of which are linked to the development of metabolic diseases such as diabetes and hypertension in the general population.[27] [28] [29] [30] Similarly, ANS dysfunction has been repeatedly implicated as a likely underlying biomechanism linking PTSD and metabolic dysfunction.[31] Key PTSD symptoms such as re-experiencing, where an individual involuntarily relives the traumatic event via flashbacks and nightmares,[32] and hyperarousal, a cluster of symptoms including hypervigilance and heightened startle reaction, are associated with increased release of norepinephrine, low HRV, and high blood pressure,[33] [34] [35] indicating that ANS dysfunction may contribute to the high comorbidity between PTSD and metabolic dysfunction in nonpregnant individuals.[36] [37]

Fig. 1 Parallel impacts of trauma and PTSD (A) and pregnancy (B) on physiology. (A) Trauma exposure and PTSD lead to dysregulation of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (ANS) axis. Downstream, dysregulation of the major stress axes leads to an increase in inflammatory markers and dysregulation in metabolic processes such as glucose and insulin production and sensitivity, leptin release and lipogenesis. (B) SNS and HPA axis adaptations during gestation. Normal pregnancy is accompanied by adaptive physiological shifts in both the SNS and HPA axis, including a reduction in HRV and an increase in cortisol and ACTH, respectively. To accommodate increasing fetal energy demands, gestation is also accompanied by hyperglycemia and insulin resistance. To prevent rejection of the growing fetus by the pregnant person's immune system, there is a shift toward an anti-inflammatory state during the second and third trimester of pregnancy. Illustration by Bona Kim; reproduced with permission of ©Emory University. HRV, heart rate variability; PTSD, posttraumatic stress disorder.

HPA Axis Dysregulation and Adverse Impacts on Metabolic Function

Exposure to repeated traumatic stressors leads to dysregulation of the HPA axis and increased glucocorticoid release ([Fig. 1A]).[19] Chronic exposure to elevated glucocorticoids deteriorates the negative feedback control of the HPA axis via down-regulation of glucocorticoid receptor expression in the brain.[38] Disinhibition of glucocorticoid release then leads to a chronic catabolic state, where there is continuous increase of glucose production, degradation of protein and muscle mass, and antagonization of anabolic hormones.[39] Additionally, trauma exposure is also associated with decreased levels of neuropeptide Y (NPY), an orexigenic neuropeptide that also has anxiolytic properties.[40] Together, such neuroendocrine changes have detrimental effects on metabolism, namely leading to a decrease in lean body mass, an increase in visceral body fat, and the development of hyperglycemia and insulin resistance.[41] [42] [43] Left untreated, such metabolic changes can progress into metabolic disorders in nonpregnant populations.[44] [45]

The development and maintenance of PTSD symptoms are due in part to altered HPA axis function.[46] [47] Alterations in glucocorticoid function have been described in individuals with PTSD, including reduced glucocorticoid response to acute stressors,[48] elevated glucocorticoid receptor levels,[49] and an enhanced glucocorticoid negative feedback mechanism.[50] PTSD is also associated with low baseline levels of NPY.[51] Animal studies also suggest that increased sensitivity of the glucocorticoid receptor, as is found in PTSD, upregulates gene expression of genes implicated in metabolic pathways, including NPY and adiponectin 1, key regulators of appetite and insulin sensitivity, respectively.[52] [53] Similar neuroendocrine changes have been described in obesity and metabolic syndrome in the general population, metabolic disorders that are highly comorbid with PTSD in trauma-exposed persons.[16] [54] It remains unclear, however, whether HPA axis dysregulation may induce behavioral changes in appetite and physical activity in individuals with trauma and PTSD that contribute to metabolic dysfunction.

Increased Inflammation Resulting from ANS and HPA dysfunction and Impacts on Metabolic Function

ANS and HPA axis dysregulation leads to heightened systemic inflammation that has detrimental impacts on multiple physiological functions, including metabolism ([Fig. 1A]).[55] Under chronic stress conditions, the HPA axis releases an excess of cortisol,[56] which enhances the expression of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18.[57] Concurrently, heightened norepinephrine release as a result traumatic stress exposure promotes the secretion of inflammatory factors including tumor necrosis factor α (TNFα), a major regulator of the inflammatory response, and IL-6, a pro-inflammatory cytokine.[58] [59]

The ANS and HPA-axis dysregulation present in PTSD can also result in increased systemic inflammation.[60] For example, elevated serum catecholamines characteristic of PTSD are associated with an increase in pro-inflammatory mediators, primarily prostaglandins.[61] Individuals with PTSD show higher concentrations of C-reactive protein (CRP), IL-6),[62] IL-1b,[63] as well as greater gene expression and activity of nuclear factor-kappa betta (NF-kB), a master transcriptional activator of pro-inflammatory markers that is regulated by glucocorticoid receptor activity.[64] [65] Additionally, polymorphisms in inflammatory genes, such as CRP, are associated with increased risk for augmented systemic inflammation,[66] as well as PTSD and psychophysiological hyperarousal in trauma-exposed individuals.[67] This excess pro-inflammatory activity in PTSD is coincident with increased levels of inflammation in metabolic disease including T2DM.[68]

Overall, existing data suggest that traumatic events and PTSD act as chronic stressors to impact metabolism in nonpregnant individuals via ANS and HPA-axis dysregulation and heightened systemic inflammation. Augmented levels of IL-6, IL-1β, and TNFα contribute to insulin resistance and hyperglycemia in people with T2DM,[69] [70] while IL-18 is closely associated with metabolic syndrome.[71] This suggests that trauma exposure and resulting PTSD may be two psychosocial risk factors that may contribute to racial-ethnic health disparities in gestational metabolic dysfunction. In the following section, we will review what is currently known regarding the relationships between trauma, PTSD, and gestational metabolic dysfunction in pregnant individuals.

Stress and Metabolic Dysfunction in Pregnancy

Pregnancy is a period of metabolic adaptations directed toward meeting dynamic maternal–fetal energy requirements ([Fig. 1B]).[35] [72] Metabolic adaptations in pregnancy are divided into anabolic and catabolic stages, the first which involves maternal accumulation of fat and nutrient stores during the beginning two trimesters of pregnancy, followed by a breakdown of lipid reserves and transferring of nutrients to the rapidly growing fetus during the third trimester.[72] [73] [74] Normal pregnancy shifts the activity of the major stress systems, leading to reduction in HRV via the SNS and increase in cortisol and ACTH secretion by the HPA-axis.[75] [76] [77] To meet dynamic energy demands of both the growing fetus and pregnant person, gestation induces hyperglycemia and insulin resistance.[78] [79] Lastly, during the last two trimesters of pregnancy, the pregnant person's immune system shifts toward an anti-inflammatory state to prevent rejection of the fetus.[80] [81] While these metabolic shifts are essential to the survival of the maternal–fetal unit, adaptations may surpass normal pregnancy parameters, leading to gestational metabolic dysfunction and in more severe cases, gestational metabolic disorders.[82] Among factors that can contribute to gestational metabolic dysfunction, trauma and PTSD warrant further exploration.

Relationships between Trauma, PTSD, and Gestational Diabetes Mellitus

GDM is a subtype of diabetes seen in pregnant people without preexisting diabetes characterized by exaggerated disinhibition of glucose production.[83] In normal pregnancy, there is a transfer of glucose from pregnant person to fetus via simple and facilitated diffusion through the placenta. This process occurs in stages, beginning with pancreatic β-cell hyperplasia during early pregnancy to increase insulin release and maintain glucose tolerance at a normal or slightly improved level, as compared with an individual's nonpregnant state.[84] During the second half of gestation, to increase glucose supply for the growing fetus there is a decrease in maternal insulin sensitivity.[85] To counter insulin resistance inherent to pregnancy, the pregnant person's body upregulates insulin production, a process believed to occur through the expansion of pancreatic β-cells.[86] In GDM, however, such compensatory mechanism is insufficient, leading to the pregnant person being unable to upregulate insulin production to counter gestational insulin resistance, resulting in hyperglycemia.[87]

Similar to hyperglycemia in nonpregnant populations, trauma and PTSD are associated with GDM ([Table 1]). A current PTSD diagnosis is associated with an increased risk of GDM in a large, racially diverse sample of pregnant veterans.[88] Associations between early life trauma and GDM, however, are equivocal such that one study suggests an almost 30 to 40% increased risk for GDM among a white population with severe childhood physical abuse,[89] and on the contrary, another suggested this association only with the presence of prepregnancy depression in a similar demographic group.[90] However, only one of these studies[90] controlled for previous GDM and diet, two key risk factors for the development of GDM.

Table 1 Relationship between trauma, PTSD, chronic stress, and GDM

GDM
	Reference	Stress/trauma subtype	Association with GDM	Sample size (N)	Racial-ethnic demographics	Income	Education
Trauma	Mason et al, 2016	Early life abuse	↑	45,550	NW: 46%	Not reported	SC + : 100%
	Schoenaker et al, 2019	Adverse childhood experiences	—	6,317	Not reported	Not reported	<HS: 21.4% SC: 21.5% C: 57.1%
PTSD	Shaw et al, 2017	PTSD in pregnant veterans	↑	15,986	W, NH: 64.2% B, NH: 23% O: 11%	Not reported	Not reported
Chronic stress	Hosler et al, 2011	>5 stressful events 12 months before birth	↑	2,690	W, NH: 73.4% B, NH: 9.1% H: 12.1% A: 3.1% O: 2.2%	Not reported	<HS: 15.3% HS: 22.4% SC + : 62.3%
	Records et al, 2015	Any chronic stressor 12 months before birth	—	3,655	W, NH: 85.5% H: 1.2%	Not reported	<HS: 10.9% HS: 19.3% SC: 39.4 SC + : 30.4
	Silveira et al, 2014	Increase in stress during pregnancy	↑	1,115	H: 100%	Less than or equal to 15k: 28.6% 15k–30k: 14.4%; greater than or equal to 30k: 6.8%	<HS: 45.9% HS: 31.3% SC + : 18.8%
	Mishra et al, 2020	Antenatal stress	↑	373	A: 100%	No info	<HS: 49.2% HS + : 23.7%
	MacGregor et al, 2020	Perceived discrimination	↑	595	W, NH: 61.8% B, NH: 16.6% H: 15.6% O: 5.8%	Less than or equal to 15k: 14.6% >15k–50k: 34.79 >100K: 22%	Less than or equal to HS: 32.2% SC: 24.2% C/C + : 43.3%

Abbreviations: GDM, gestational diabetes mellitus; PTSD, posttraumatic stress disorder.

Note: Race and ethnicity: W, NH: white non-Hispanic; B, NH: black non-Hispanic; H: Hispanic; A: Asian; I: indigenous; O: other; MR: multiracial; NW: non-white.

Education: <HS: less than high school; HS: high school; SC: some college; SC + : some college or more; C: college; G: graduate school; T: training program/certification.

↑: positive association found; —: no association found.

The associations between trauma or PTSD and GDM are further supported by studies that have established a relationship between nontraumatic chronic stressors and GDM. For example, increases in perceived psychosocial stress from early to mid-pregnancy is associated with a 2.6-fold increased odds of GDM and an increase in glucose level in a majority low-income Hispanic sample.[91] Similarly, the odds of GDM are 13-fold higher among individuals with high antenatal perceived stress compared with individuals with low antenatal stress in a sample of women from Karnataka, India.[92] Moreover, in a racially diverse sample, perceived discrimination is associated with increased risk of developing GDM.[93] Experiencing greater than five stressful events (including financial and job issues, interpersonal problems, moving, etc.) within 12 months before birth is associated with GDM in a primarily white and college-educated sample.[94] However, a study with similar demographics found no association between chronic stress 12 months before birth and GDM.[95]

Relationships between Trauma, PTSD and Low Birth Weight and Fetal Growth Restriction

LBW is defined as infant birthweight of less than 2,000 g. Infants with LBW are at an increased risk of chronic illnesses later in life including diabetes and hypertension.[96] In cases when LBW falls below the 10th percentile for gestational age, infants are diagnosed with FGR. FGR impacts 5 to 10% of pregnancies in which the fetus fails to reach its growth potential in utero and affects essential bodily functions in offspring including breathing, immunity, and cognition, making it a particularly dangerous pregnancy complication.[97] The metabolic origins of LBW and FGR are complicated, with studies implicating reduced supply of nutrients,[98] higher maternal–fetal glucose concentrations,[99] and reduced amino acid delivery[100] in the development of LBW and FGR. Seeking to uncover psychosocial risk factors, a handful of studies have explored the connection between trauma, PTSD, and risk for LBW and FGR.

Existing literature suggests that trauma and PTSD are associated with LBW but not FGR ([Table 2]). Racial trauma, specifically experiencing or witnessing racism during childhood, leads to an increase in diastolic blood pressure during the last two trimesters of pregnancy, which is associated with LBW in a sample of black American women.[101] Similarly, high maternal lifetime traumatic stress (e.g., natural disasters, childhood maltreatment, interpersonal violence, sexual assault) resulting in increased prenatal hair cortisol is associated with infant LBW but not FGR in male offspring in a study within a primarily low-income Hispanic and black sample.[102] PTSD diagnosis is associated with LBW but not FGR in a racially diverse sample of Hurricane Katrina survivors.[103] Similarly, in a large sample of displaced Pakistani women, PTSD is independently associated with LBW.[104] PTSD resulting from intimate partner violence has also been associated with LBW in a racially diverse and majority low-income study cohort.[105] In contrast, a study conducted in a Latinx population with variable trauma type exposures found no association with PTSD and LBW, but did find a relationship between PTSD diagnosis and preterm delivery.[106] Equivocal findings in these two studies may be due to use of different PTSD measures, a long-form scale adapted from the University of Michigan Composite International Diagnostic review[105] and the PTSD Checklist-Civilian Version,[106] respectively.

Table 2 Relationship between trauma, PTSD, chronic stress, and LBW or FGR

LBW and FGR
	Reference	Stress/trauma subtype	Association with LBW	Association with FGR	Sample size (N)	Racial-ethnic demographics	Income	Education
Trauma	Hilmert et al, 2014	Childhood racial trauma	↑		39	B, NH: 100%	2,350 (167) reported as mean (SD)	>HS: 35.9% SC: 46.2% C: 15.4% G: 2.6%
	Flom et al, 2018	Lifetime traumatic stress	↑	—	314	W, NH: 33% B, NH: 26% H: 41%	Majority lower income	Less than or equal to 12: 63% Greater than 12: 37% reported in years
PTSD	Rosen et al, 2007	PTSD due to intimate partner violence	↑		148	B, NH: 54.1%	73% low income	35.4% >HS
	Gelaye et al, 2020	PTSD due to variable trauma	⏤		4,408	H: 77.8%	Not reported	<6: 2.9%; 7–12: 49.9%; >12: 47.2%
	Xiong et al, 2008	PTSD due to natural disasters	↑		219	W, NH: 53.8% B, NH: 41.6% O:14.6%	<20k: 24.9% 20k–60k: 39% >60k: 36.1%	Not reported
	Rashid et al, 2020	PTSD in war-displaced women	↑		450	A: 100%	<10k Pakistani rupee: 72%	<5: 59% (reported in years)
Chronic stress	Rondó et al, 2003	Psychosocial stress during 2nd and 3rd trimester	↑	—	865	H: 100%	0–1: 24% 1–2: 34.7% 2–3%: 20% >3: 21.3% - reported as per capita income	<4: 8.9% 4–8: 57.0% >8: 34.1% reported in years
	Brown et al, 2019	Perceived medical discrimination	↑		344	I: 100%	Not reported	>HS: 47.5% T: 46.0% C: 6.5%

Abbreviations: FGR, fetal growth restriction; LBW, low birth weight; PTSD, posttraumatic stress disorder.

Note: Race and ethnicity: W, NH: white non-Hispanic; B, NH: black non-Hispanic; H: Hispanic; A: Asian; I: indigenous; O: other; MR: multiracial; NW: non-white.

Education: <HS: less than high school; HS: high school; SC: some college; SC + : some college or more; C: college; G: graduate school; T: training program/certification.

↑: positive association found; —: no association found.

The associations between trauma and PTSD and LBW are further supported by studies that have established a relationship between nontraumatic chronic stressors and GDM. For example, maternal perceived stress during the second and third trimester is associated with LBW and preterm delivery, but not FGR, in a Brazilian Latinx low-income sample.[107] Additionally, perceived medical discrimination is associated with increased risk for LBW in a cohort of Aboriginal Australian women.[108]

Relationships between Trauma, PTSD and Gestational Hypertension and Preeclampsia

GHTN is defined as persistent blood pressure readings higher than 140 mmHg systolic or 90 mmHg diastolic pressure in a woman who was normotensive prior to 20-weeks gestational age and in the absence of signs of end-organ damage.[109] GHTN causes cardiovascular insufficiency and, if left untreated, is often a precursor to the development of preeclampsia (PRE-E). PRE-E is a gestational cardiovascular disease defined as persistent severe hypertension with signs of end-organ damage following 20 weeks gestational age.[110] [111] [112] [113] PRE-E is a severe life-threatening condition that increases risk for secondary health complications including placental abruption, stroke, and seizures (eclampsia).[114]

Recent studies have explored associations between trauma and PTSD and GHTN and PRE-E ([Table 3]). PTSD is associated with both GHTN and PRE-E, while trauma is not associated with HDP. More specifically, experiencing four or more traumatic experiences during childhood (e.g., abuse, parental separation, witnessing abuse, living with a substance abuser, household member imprisonment) was not associated with the development of GHTN or PRE-E in a cohort of Latinx pregnant women.[115] However, a PTSD diagnosis is associated with an increased risk of both GHTN and PRE-E in a large, racially diverse sample of pregnant veterans.[88] Similarly, a diagnosis of PTSD stemming from experiencing inter-partner violence is associated with the development of GHTN and PRE-E in a majority black study sample.[88] [116]

Table 3 Relationships between trauma, PTSD, chronic stress, and GHTN or PRE-E

GHTN and PRE-E
	Reference	Stress/trauma subtype	Association with GHTN	Association with PRE-E	Sample size (N)	Racial-ethnic demographics	Income	Education
Trauma	Shaw et al, 2017	Traumatic exposure in war veterans		↑	14,047	W, NH: 10,262 B, NH: 3,673 O: 519	Not reported	Not reported
	Stanhope et al, 2020	Adverse childhood experiences	—		2,319	H: 100%	Not reported	<HS: 31.6% HS: 22.3% >HS: 36.4%
PTSD	Gilliam et al, 2022	Inter-partner violence (IPV) and PTSD symptoms during pregnancy	↑		137	B, NH: 69.9% W, NH: 18.4 MR: 8.1% H: 7.4% O: 0.7%	Majority low income	Not reported
	Shaw et al, 2017	PTSD and associated symptoms		↑	14,047	W, NH: 10,262 B, NH: 3,673 O: 519	Not reported	Not reported
Chronic stress	Leeners et al, 2007	Emotional stress	↑		1,605	W: 100%	Not reported	< Elementary school: 0.62%, Extended elementary school: 12.6% HS: 36.9. >HS: 49.9
	Vollebregt et al, 2008	Psychosocial stress	—	—	12,377	W, NH: 2,461 B, NH: 157 Turkish/Moroccan: 347 O: 712	Not reported	0–5: 557, 6–10: 1,445, >10: 1,651 Reported in years of education
	Klonoff-Cohen et al, 1996	Job stress		↑	218	W, NH: 58% B, NH: 42%	Not reported	12: 40.8% 12 + : 65.6% Reported in years of education
	Schneider et al, 2011	Psychosocial Stress		↑	647,392	Not reported	Not reported	Not reported
	Marcoux et al, 1999	Job stress during first 20 weeks of pregnancy	↑	↑	730	Not reported	Not reported	Less than or equal to 12: 50% 13–14: 18.9% Greater than or equal to 15: 31.1% Reported in years of education
	Caplan et al, 2021	Lifetime stress	↑	↑	744	W, NH: 59.1% B, NH:16.3% H: 18.7%	Not reported	<HS: 26% C + : 39.5%

Abbreviations: GHTN, gestational hypertension; PRE-E, precursor to the development of preeclampsia; PTSD, posttraumatic stress disorder.

Note: Race and ethnicity: W,NH: white non-Hispanic; B, NH: black non-Hispanic; H: Hispanic; A: Asian; I: indigenous; O: other; MR: multiracial; NW: non-white.

Education: <HS: less than high school; HS: high school; SC: some college; SC + : some college or more; C: college; G: graduate school; T: training program/certification.

↑: positive association found; —: no association found.

While literature assessing the role of trauma or PTSD in the development of GHTN and PRE-E is limited, other studies have established a relationship between nontraumatic chronic stressors and GHTN or PRE-E. Lifetime stress, for example, increased the risk of developing GHTN or PRE-E in a majority white multi-site sample of pregnant women.[117] In parallel, lifetime chronic stress secondary to racial discrimination in a sample of black pregnant women was associated with GHTN.[101] Experiencing lifetime stressors (e.g., financial, emotional, relationship stress) was associated with an increased prevalence of HDP.[118] Furthermore, having an occupation with high mental stress was associated with an increased risk of developing PRE-E in a sample of Canadian women,[119] and job-related stress during pregnancy increased the risk for PRE-E in a black and white sample.[120] Social burden, defined as low social status and high psychosocial stress, was associated with PRE-E development in a cohort of pregnant German women.[121] Moreover, experiencing emotional stressors (including social, psychological, financial, family, and medical stressors) during pregnancy was associated with a 1.6-fold increased risk for developing a hypertensive disease in pregnancy in a white study cohort.[122] Conversely, a study conducted in the Netherlands in a primarily white sample determined that psychological stress (including work stress, depression, anxiety, and pregnancy-related anxiety) in the first trimester had no significant influence on the incidence of PRE-E in nulliparous women.[123]

Conclusions and Future Directions

In summary, the limited existing literature supports the premise that trauma and PTSD may be important factors that impact metabolic function within the context of pregnancy, as trauma exposure and PTSD are associated with increased risk of gestational metabolic dysfunction ([Tables 1] [2] [3]). However, further work is needed to characterize the specific biological mechanisms that underlie how trauma and PTSD can contribute to the development of metabolic disorders of pregnancy. Specifically, no known studies have investigated associations between gestational metabolic disorders and biological markers of chronic stress or trauma (e.g., cortisol, HRV) or physiological measures of PTSD severity (e.g., hyperarousal), despite evidence of a relationship between such biological markers and metabolic disorders in nonpregnant persons ([Fig. 1]).[124] [125]

Importantly, many of the existing studies failed to consider key confounders in the relationship between trauma or PTSD and gestational metabolic disease in pregnancy. For instance, despite genetic predisposition being one of the biggest risk factors for gestational metabolic disease,[126] [127] several of the included studies did not consider family history as a confounding variable.[4] [77] [88] [101] [102] [104] [116] Moreover, not all studies controlled for preexisting metabolic disease[88] [105] [106] and previous gestational metabolic disease.[102] [105] [106] [116] Specific to GDM, diet and having a sedentary lifestyle,[128] [129] are some of the biggest risk factors of GDM; however, only one of the three included studies controlled for these factors in their analyses.[90] For FGR and LBW, food insufficiency, which causes undernutrition,[130] and substance abuse, which limits uterine and placental blood flow necessary for fetal growth,[131] were each controlled for in only two out of the six included studies.[103] [105] [106] Finally, few of the existing studies considered how behavioral changes following trauma or onset of PTSD, including changes in sleep, physical activity, and eating behaviors, impact metabolism during pregnancy.[128] [129]

The equivocal nature of some studies assessing risk for HDP due to PTSD may be due to inconsistent measures of PTSD used across studies. Studies to date have used the Mini International Neuropsychiatric interview[105] and the Posttraumatic Stress Disorder Checklist,[106] which are self-report measures, and the International Classification of Disease, Ninth Revision (ICD-9),[88] a clinician-administered diagnosis of PTSD. Self-report measures have been found to result in higher severity scores as compared with scores from clinician-administered measures. Additionally, the cutoff score for PTSD diagnosis using the same self-report measure is inconsistent across study groups.[132] Conversely, clinician-administered PTSD measures like the ICD-9 require access to mental health care. This is an important caveat to consider, as previous studies have found that socioeconomically disadvantaged and minoritized women are underdiagnosed for PTSD.[133] The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a psychometrically valid and standardized alternative to measures used in studies to date that has shown excellent reliability for over 20 years.[134] Future studies would benefit from using the most rigorous instruments to quantify PTSD symptoms, traumatic events, and chronic stressors like racial discrimination.

In the current review, we included various trauma types when assessing the relationship between trauma and gestational metabolic disease. However, different trauma types may have distinct impacts on the ANS and HPA-axis as well as on metabolism in and outside the context of pregnancy. For instance, childhood maltreatment, has been consistently shown to have deleterious effects on cardiometabolic health in nonpregnant people.[135] [136] [137] Childhood sexual abuse, in particular, has been associated with metabolic risk factors including low HRV and higher body mass index,[138] highlighting the need for future studies to consider how different types of trauma impact gestational metabolic function and risk for HPD.

Another important limitation of existing studies assessing the relationships between trauma, PTSD, and metabolic disorders in pregnancy is the lack of representation of racial-ethnic minorities (see all tables). Given the disproportionate impact of gestational metabolic disorders on people of color, in particular black pregnant persons,[8] studies that aim to identify risk factors for gestational metabolic dysfunction would benefit greatly from having representative study samples. As a result of interpersonal, systemic, and institutional racism, non-white persons, especially black persons, are exposed to greater levels of chronic stress, traumatic experiences, and are more likely to be diagnosed with PTSD, suggesting that these exposures may be risk factors for gestational metabolic disease.[11] [12] [13] [14] [139] Due to maternal health inequities, there is a critical need to understand the biological mechanisms underlying the relationship between chronic stress, trauma, PTSD, and gestational metabolic disease. This research could aid with early identification of pregnant individuals at high risk for gestational metabolic disease, allowing for preventive and early treatment to improve maternal health inequities and associated disease in their offspring.

• References

• 1 Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005; 115 (05) 1111-1119
• 2 Sheehy S, Aparicio HJ, Xu N. et al. Hypertensive disorders of pregnancy and risk of stroke in US black women. NEJM Evid 2023; 2 (10) EVIDoa2300058
• 3 Miller EC, Zambrano Espinoza MD, Huang Y. et al. Maternal race/ethnicity, hypertension, and risk for stroke during delivery admission. J Am Heart Assoc 2020; 9 (03) e014775
• 4 Ben-Haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes. Diabet Med 2004; 21 (02) 103-113
• 5 Zhang C, Ning Y. Effect of dietary and lifestyle factors on the risk of gestational diabetes: review of epidemiologic evidence. Am J Clin Nutr 2011; 94 (6, suppl): 1975S-1979S
• 6 Cunningham F. Fetal growth disorders. In: Williams Obstetrics. New York USA: McGraw-Hill Professional Publishing; 2010: 881-910
• 7 Albu AR, Anca AF, Horhoianu VV, Horhoianu IA. Predictive factors for intrauterine growth restriction. J Med Life 2014; 7 (02) 165-171
• 8 Ross KM, Dunkel Schetter C, McLemore MR. et al. Socioeconomic status, preeclampsia risk and gestational length in black and white women. J Racial Ethn Health Disparities 2019; 6 (06) 1182-1191
• 9 Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62 (06) 617-627
• 10 Noushad S, Ahmed S, Ansari B, Mustafa UH, Saleem Y, Hazrat H. Physiological biomarkers of chronic stress: a systematic review. Int J Health Sci (Qassim) 2021; 15 (05) 46-59
• 11 Boen CE, Hummer RA. Longer—but harder—lives?: The Hispanic health paradox and the social determinants of racial, ethnic, and immigrant–native health disparities from midlife through late life. J Health Soc Behav 2019; 60 (04) 434-452
• 12 Gillespie CF, Bradley B, Mercer K. et al. Trauma exposure and stress-related disorders in inner city primary care patients. Gen Hosp Psychiatry 2009; 31 (06) 505-514
• 13 Pole N, Best SR, Metzler T, Marmar CR. Why are hispanics at greater risk for PTSD?. Cultur Divers Ethnic Minor Psychol 2005; 11 (02) 144-161
• 14 Schwartz AC, Bradley RL, Sexton M, Sherry A, Ressler KJ. Posttraumatic stress disorder among African Americans in an inner city mental health clinic. Psychiatr Serv 2005; 56 (02) 212-215
• 15 Farr OM, Sloan DM, Keane TM, Mantzoros CS. Stress- and PTSD-associated obesity and metabolic dysfunction: a growing problem requiring further research and novel treatments. Metabolism 2014; 63 (12) 1463-1468
• 16 Michopoulos V, Vester A, Neigh G. Posttraumatic stress disorder: a metabolic disorder in disguise?. Exp Neurol 2016; 284 (Pt B): 220-229
• 17 Russell G, Lightman S. The human stress response. Nat Rev Endocrinol 2019; 15 (09) 525-534
• 18 McCorry LK. Physiology of the autonomic nervous system. Am J Pharm Educ 2007; 71 (04) 78
• 19 Herman JP, McKlveen JM, Ghosal S. et al. Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol 2016; 6 (02) 603-621
• 20 Magomedova L, Cummins CL. Glucocorticoids and metabolic control. Handb Exp Pharmacol 2016; 233: 73-93
• 21 Tapp ZM, Godbout JP, Kokiko-Cochran ON. A tilted axis: maladaptive inflammation and HPA axis dysfunction contribute to consequences of TBI. Front Neurol 2019; 10: 345
• 22 Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 2000; 21 (01) 55-89
• 23 Rohleder N. Stress and inflammation - The need to address the gap in the transition between acute and chronic stress effects. Psychoneuroendocrinology 2019; 105: 164-171
• 24 Borges SW. Stress Science: Neuroendocrinology. Elsevier Science; San Diego CA: 2010: 306-312
• 25 Herman JP, McKlveen JM, Solomon MB, Carvalho-Netto E, Myers B. Neural regulation of the stress response: glucocorticoid feedback mechanisms. Braz J Med Biol Res 2012; 45 (04) 292-298
• 26 Morris MC, Rao U. Psychobiology of PTSD in the acute aftermath of trauma: integrating research on coping, HPA function and sympathetic nervous system activity. Asian J Psychiatr 2013; 6 (01) 3-21
• 27 Azulay N, Olsen RB, Nielsen CS. et al. Reduced heart rate variability is related to the number of metabolic syndrome components and manifest diabetes in the sixth Tromsø study 2007-2008. Sci Rep 2022; 12 (01) 11998
• 28 Williams DP, Koenig J, Carnevali L. et al. Heart rate variability and inflammation: a meta-analysis of human studies. Brain Behav Immun 2019; 80: 219-226
• 29 Dennis PA, Kimbrel NA, Sherwood A. et al. Trauma and autonomic dysregulation: episodic–versus systemic–negative affect underlying cardiovascular risk in posttraumatic stress disorder. Psychosom Med 2017; 79 (05) 496-505
• 30 Freaney PM, Harrington K, Molsberry R. et al. Temporal trends in adverse pregnancy outcomes in birthing individuals aged 15 to 44 years in the United States, 2007 to 2019. J Am Heart Assoc 2022; 11 (11) e025050
• 31 Furtado JM, Almeida SM, Mascarenhas P. et al. Anthropometric features as predictors of atherogenic dyslipidemia and cardiovascular risk in a large population of school-aged children. PLoS One 2018; 13 (06) e0197922
• 32 Risser HJ, Hetzel-Riggin MD, Thomsen CJ, McCanne TR. PTSD as a mediator of sexual revictimization: the role of reexperiencing, avoidance, and arousal symptoms. J Trauma Stress 2006; 19 (05) 687-698
• 33 Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA 2007; 298 (14) 1685-1687
• 34 Pitman RK, Orr SP, Forgue DF, de Jong JB, Claiborn JM. Psychophysiologic assessment of posttraumatic stress disorder imagery in Vietnam combat veterans. Arch Gen Psychiatry 1987; 44 (11) 970-975
• 35 Barateiro A, Mahú I, Domingos AI. Leptin resistance and the neuro-adipose connection. Front Endocrinol (Lausanne) 2017; 8: 45
• 36 Canale MP, Manca di Villahermosa S, Martino G. et al. Obesity-related metabolic syndrome: mechanisms of sympathetic overactivity. Int J Endocrinol 2013; 2013: 865965
• 37 Thorp AA, Schlaich MP. Relevance of sympathetic nervous system activation in obesity and metabolic syndrome. J Diab Res 2015; 2015: 341583
• 38 Furay AR, Bruestle AE, Herman JP. The role of the forebrain glucocorticoid receptor in acute and chronic stress. Endocrinology 2008; 149 (11) 5482-5490
• 39 Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res 2002; 53 (04) 865-871
• 40 Keen-Rhinehart E, Ondek K, Schneider JE. Neuroendocrine regulation of appetitive ingestive behavior. Front Neurosci 2013; 7: 213
• 41 Kyrou I, Chrousos GP, Tsigos C. Stress, visceral obesity, and metabolic complications. Ann N Y Acad Sci 2006; 1083 (01) 77-110
• 42 McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin 2001; 17 (01) 107-124
• 43 Kang W, Tong T, Park T. Corticotropin releasing factor-overexpressing mouse is a model of chronic stress-induced muscle atrophy. PLoS One 2020; 15 (02) e0229048
• 44 Morris T, Moore M, Morris F. Stress and chronic illness: the case of diabetes. J Adult Dev 2011; 18 (02) 70-80
• 45 Spruill TM. Chronic psychosocial stress and hypertension. Curr Hypertens Rep 2010; 12 (01) 10-16
• 46 Jovanovic T, Ressler KJ. How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD. Am J Psychiatry 2010; 167 (06) 648-662
• 47 Dunlop BW, Wong A. The hypothalamic-pituitary-adrenal axis in PTSD: Pathophysiology and treatment interventions. Prog Neuropsychopharmacol Biol Psychiatry 2019; 89: 361-379
• 48 Kolassa I-T, Eckart C, Ruf M, Neuner F, de Quervain DJ, Elbert T. Lack of cortisol response in patients with posttraumatic stress disorder (PTSD) undergoing a diagnostic interview. BMC Psychiatry 2007; 7 (01) 54
• 49 Matić G, Milutinović DV, Nestorov J. et al. Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD. Prog Neuropsychopharmacol Biol Psychiatry 2013; 43: 238-245
• 50 Yehuda R, Boisoneau D, Lowy MT, Giller Jr EL. Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. Arch Gen Psychiatry 1995; 52 (07) 583-593
• 51 Rasmusson AM, Schnurr PP, Zukowska Z, Scioli E, Forman DE. Adaptation to extreme stress: post-traumatic stress disorder, neuropeptide Y and metabolic syndrome. Exp Biol Med (Maywood) 2010; 235 (10) 1150-1162
• 52 Beck B. Neuropeptide Y in normal eating and in genetic and dietary-induced obesity. Philos Trans R Soc Lond B Biol Sci 2006; 361 (1471): 1159-1185
• 53 Whitehead JP, Richards AA, Hickman IJ, Macdonald GA, Prins JB. Adiponectin–a key adipokine in the metabolic syndrome. Diabetes Obes Metab 2006; 8 (03) 264-280
• 54 Muhie S, Gautam A, Meyerhoff J, Chakraborty N, Hammamieh R, Jett M. Brain transcriptome profiles in mouse model simulating features of post-traumatic stress disorder. Mol Brain 2015; 8 (01) 14
• 55 Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65 (09) 732-741
• 56 Elenkov IJ. Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. Neurochem Int 2008; 52 (1–2): 40-51
• 57 Busillo JM, Azzam KM, Cidlowski JA. Glucocorticoids sensitize the innate immune system through regulation of the NLRP3 inflammasome. J Biol Chem 2011; 286 (44) 38703-38713
• 58 Bellinger DL, Millar BA, Perez S. et al. Sympathetic modulation of immunity: relevance to disease. Cell Immunol 2008; 252 (1–2): 27-56
• 59 Pal M, Febbraio MA, Whitham M. From cytokine to myokine: the emerging role of interleukin-6 in metabolic regulation. Immunol Cell Biol 2014; 92 (04) 331-339
• 60 Yang J-J, Jiang W. Immune biomarkers alterations in post-traumatic stress disorder: a systematic review and meta-analysis. J Affect Disord 2020; 268: 39-46
• 61 Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system (1987-2007). Brain Behav Immun 2007; 21 (06) 736-745
• 62 Maes M, Lin AH, Delmeire L. et al. Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biol Psychiatry 1999; 45 (07) 833-839
• 63 Spivak B, Shohat B, Mester R. et al. Elevated levels of serum interleukin-1 β in combat-related posttraumatic stress disorder. Biol Psychiatry 1997; 42 (05) 345-348
• 64 O'Donovan A, Sun B, Cole S. et al. Transcriptional control of monocyte gene expression in post-traumatic stress disorder. Dis Markers 2011; 30 (2–3): 123-132
• 65 Pace TW, Wingenfeld K, Schmidt I, Meinlschmidt G, Hellhammer DH, Heim CM. Increased peripheral NF-κB pathway activity in women with childhood abuse-related posttraumatic stress disorder. Brain Behav Immun 2012; 26 (01) 13-17
• 66 Kathiresan S, Larson MG, Vasan RS. et al. Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level. Circulation 2006; 113 (11) 1415-1423
• 67 Michopoulos V, Rothbaum AO, Jovanovic T. et al. Association of CRP genetic variation and CRP level with elevated PTSD symptoms and physiological responses in a civilian population with high levels of trauma. Am J Psychiatry 2015; 172 (04) 353-362
• 68 Steven S, Frenis K, Oelze M. et al. Vascular inflammation and oxidative stress: major triggers for cardiovascular disease. Oxid Med Cell Longev 2019; 2019: 7092151
• 69 Daniele G, Guardado Mendoza R, Winnier D. et al. The inflammatory status score including IL-6, TNF-α, osteopontin, fractalkine, MCP-1 and adiponectin underlies whole-body insulin resistance and hyperglycemia in type 2 diabetes mellitus. Acta Diabetol 2014; 51 (01) 123-131
• 70 Dinarello CA, Donath MY, Mandrup-Poulsen T. Role of IL-1β in type 2 diabetes. Curr Opin Endocrinol Diabetes Obes 2010; 17 (04) 314-321
• 71 Trøseid M, Seljeflot I, Arnesen H. The role of interleukin-18 in the metabolic syndrome. Cardiovasc Diabetol 2010; 9 (01) 11
• 72 Zeng Z, Liu F, Li S. Metabolic adaptations in pregnancy: a review. Ann Nutr Metab 2017; 70 (01) 59-65
• 73 Herrera E. Metabolic adaptations in pregnancy and their implications for the availability of substrates to the fetus. Eur J Clin Nutr 2000; 54 (1, suppl 1): S47-S51
• 74 Parrettini S, Caroli A, Torlone E. Nutrition and metabolic adaptations in physiological and complicated pregnancy: focus on obesity and gestational diabetes. Front Endocrinol (Lausanne) 2020; 11: 611929
• 75 Stein PK, Hagley MT, Cole PL, Domitrovich PP, Kleiger RE, Rottman JN. Changes in 24-hour heart rate variability during normal pregnancy. Am J Obstet Gynecol 1999; 180 (04) 978-985
• 76 Vegiopoulos A, Herzig S. Glucocorticoids, metabolism and metabolic diseases. Mol Cell Endocrinol 2007; 275 (1–2): 43-61
• 77 Tuckermann JP, Kleiman A, McPherson KG, Reichardt HM. Molecular mechanisms of glucocorticoids in the control of inflammation and lymphocyte apoptosis. Crit Rev Clin Lab Sci 2005; 42 (01) 71-104
• 78 Di Cianni G, Miccoli R, Volpe L, Lencioni C, Del Prato S. Intermediate metabolism in normal pregnancy and in gestational diabetes. Diabetes Metab Res Rev 2003; 19 (04) 259-270
• 79 Catalano PM, Tyzbir ED, Roman NM, Amini SB, Sims EA. Longitudinal changes in insulin release and insulin resistance in nonobese pregnant women. Am J Obstet Gynecol 1991; 165 (6, Pt 1): 1667-1672
• 80 Faas MM, Spaans F, De Vos P. Monocytes and macrophages in pregnancy and pre-eclampsia. Front Immunol 2014; 5: 298
• 81 Brown MB, von Chamier M, Allam AB, Reyes L. M1/M2 macrophage polarity in normal and complicated pregnancy. Front Immunol 2014; 5: 606
• 82 Catalano PM. Trying to understand gestational diabetes. Diabet Med 2014; 31 (03) 273-281
• 83 Johns EC, Denison FC, Norman JE, Reynolds RM. Gestational diabetes mellitus: mechanisms, treatment, and complications. Trends Endocrinol Metab 2018; 29 (11) 743-754
• 84 Parsons JA, Brelje TC, Sorenson RL. Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion. Endocrinology 1992; 130 (03) 1459-1466
• 85 Cousins L. Insulin sensitivity in pregnancy. Diabetes 1991; 40 (Suppl. 02) 39-43
• 86 Nielsen JH. Beta cell adaptation in pregnancy: a tribute to Claes Hellerström. Ups J Med Sci 2016; 121 (02) 151-154
• 87 Alfadhli EM. Gestational diabetes mellitus. Saudi Med J 2015; 36 (04) 399-406
• 88 Shaw JG, Asch SM, Katon JG. et al. Post-traumatic stress disorder and antepartum complications: a novel risk factor for gestational diabetes and preeclampsia. Paediatr Perinat Epidemiol 2017; 31 (03) 185-194
• 89 Mason SM, Tobias DK, Clark CJ, Zhang C, Hu FB, Rich-Edwards JW. Abuse in childhood or adolescence and gestational diabetes: a retrospective cohort study. Am J Prev Med 2016; 50 (04) 436-444
• 90 Schoenaker DAJM, Callaway LK, Mishra GD. The role of childhood adversity in the development of gestational diabetes. Am J Prev Med 2019; 57 (03) 302-310
• 91 Silveira ML, Whitcomb BW, Pekow P. et al. Perceived psychosocial stress and glucose intolerance among pregnant Hispanic women. Diabetes Metab 2014; 40 (06) 466-475
• 92 Mishra S, Shetty A, Rao CR, Nayak S, Kamath A. Effect of maternal perceived stress during pregnancy on gestational diabetes mellitus risk: a prospective case-control study. Diabetes Metab Syndr 2020; 14 (05) 1163-1169
• 93 MacGregor C, Freedman A, Keenan-Devlin L. et al. Maternal perceived discrimination and association with gestational diabetes. Am J Obstet Gynecol MFM 2020; 2 (04) 100222
• 94 Hosler AS, Nayak SG, Radigan AM. Stressful events, smoking exposure and other maternal risk factors associated with gestational diabetes mellitus. Paediatr Perinat Epidemiol 2011; 25 (06) 566-574
• 95 Wilson BL, Dyer JM, Latendresse G, Wong B, Baksh L. Exploring the psychosocial predictors of gestational diabetes and birth weight. J Obstet Gynecol Neonatal Nurs 2015; 44 (06) 760-771
• 96 Goldenberg RL, Culhane JF. Low birth weight in the United States. Am J Clin Nutr 2007; 85 (02) 584S-590S
• 97 Bamfo JE, Odibo AO. Diagnosis and management of fetal growth restriction. J Pregnancy 2011; 2011: 640715
• 98 Cetin I, Alvino G. Intrauterine growth restriction: implications for placental metabolism and transport. A review. Placenta 2009; 30 (suppl A): S77-S82
• 99 Marconi AM, Paolini C, Buscaglia M, Zerbe G, Battaglia FC, Pardi G. The impact of gestational age and fetal growth on the maternal-fetal glucose concentration difference. Obstet Gynecol 1996; 87 (06) 937-942
• 100 Sibley CP, Turner MA, Cetin I. et al. Placental phenotypes of intrauterine growth. Pediatr Res 2005; 58 (05) 827-832
• 101 Hilmert CJ, Dominguez TP, Schetter CD. et al. Lifetime racism and blood pressure changes during pregnancy: implications for fetal growth. Health Psychol 2014; 33 (01) 43-51
• 102 Flom JD, Chiu YM, Hsu HL. et al. Maternal lifetime trauma and birthweight: effect modification by in utero cortisol and child sex. J Pediatr 2018; 203: 301-308
• 103 Xiong X, Harville EW, Mattison DR, Elkind-Hirsch K, Pridjian G, Buekens P. Exposure to Hurricane Katrina, post-traumatic stress disorder and birth outcomes. Am J Med Sci 2008; 336 (02) 111-115
• 104 Rashid HU, Khan MN, Imtiaz A, Ullah N, Dherani M, Rahman A. Post-traumatic stress disorder and association with low birth weight in displaced population following conflict in Malakand division, Pakistan: a case control study. BMC Pregnancy Childbirth 2020; 20 (01) 166
• 105 Rosen D, Seng JS, Tolman RM, Mallinger G. Intimate partner violence, depression, and posttraumatic stress disorder as additional predictors of low birth weight infants among low-income mothers. J Interpers Violence 2007; 22 (10) 1305-1314
• 106 Gelaye B, Sanchez SE, Andrade A. et al. Association of antepartum depression, generalized anxiety, and posttraumatic stress disorder with infant birth weight and gestational age at delivery. J Affect Disord 2020; 262: 310-316
• 107 Rondó PH, Ferreira RF, Nogueira F, Ribeiro MC, Lobert H, Artes R. Maternal psychological stress and distress as predictors of low birth weight, prematurity and intrauterine growth retardation. Eur J Clin Nutr 2003; 57 (02) 266-272
• 108 Brown SJ, Gartland D, Weetra D. et al. Health care experiences and birth outcomes: results of an Aboriginal birth cohort. Women Birth 2019; 32 (05) 404-411
• 109 Brown MA, Buddie ML. The importance of nonproteinuric hypertension in pregnancy. Hypertens Pregnancy 1995; 14 (01) 57-65
• 110 Payne B, Magee LA, von Dadelszen P. Assessment, surveillance and prognosis in pre-eclampsia. Best Pract Res Clin Obstet Gynaecol 2011; 25 (04) 449-462
• 111 Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P. SOGC Hypertension Guideline Committee. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary. J Obstet Gynaecol Can 2014; 36 (07) 575-576
• 112 Gestational Hypertension and Preeclampsia. Gestational hypertension and preeclampsia: ACOG Practice Bulletin, Number 222. Obstet Gynecol 2020; 135 (06) e237-e260
• 113 Saudan P, Brown MA, Buddle ML, Jones M. Does gestational hypertension become pre-eclampsia?. Br J Obstet Gynaecol 1998; 105 (11) 1177-1184
• 114 Karrar SA, Hong PL. Preeclampsia. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022
• 115 Stanhope KK, Cammack AL, Perreira KM. et al. Adverse childhood experiences and lifetime adverse maternal outcomes (gestational diabetes and hypertensive disorders of pregnancy) in the Hispanic Community Health Study/Study of Latinos. Ann Epidemiol 2020; 50: 1-6
• 116 Gilliam HC, Howell KH, Paulson JL, Napier TR, Miller-Graff LE. Pregnancy complications and intimate partner violence: the moderating role of prenatal posttraumatic stress symptoms. J Trauma Stress 2022; 35 (05) 1484-1496
• 117 Caplan M, Keenan-Devlin LS, Freedman A. et al. Lifetime psychosocial stress exposure associated with hypertensive disorders of pregnancy. Am J Perinatol 2021; 38 (13) 1412-1419
• 118 Morgan N, Christensen K, Skedros G, Kim S, Schliep K. Life stressors, hypertensive disorders of pregnancy, and preterm birth. J Psychosom Obstet Gynaecol 2022; 43 (01) 42-50
• 119 Marcoux S, Bérubé S, Brisson C, Mondor M. Job strain and pregnancy-induced hypertension. Epidemiology 1999; 10 (04) 376-382
• 120 Klonoff-Cohen HS, Cross JL, Pieper CF. Job stress and preeclampsia. Epidemiology 1996; 7 (03) 245-249
• 121 Schneider S, Freerksen N, Maul H, Roehrig S, Fischer B, Hoeft B. Risk groups and maternal-neonatal complications of preeclampsia--current results from the national German Perinatal Quality Registry. J Perinat Med 2011; May; 39 (03) 257-265
• 122 Leeners B, Neumaier-Wagner P, Kuse S, Stiller R, Rath W. Emotional stress and the risk to develop hypertensive diseases in pregnancy. Hypertens Pregnancy 2007; 26 (02) 211-226
• 123 Vollebregt KC, van der Wal MF, Wolf H, Vrijkotte TG, Boer K, Bonsel GJ. Is psychosocial stress in first ongoing pregnancies associated with pre-eclampsia and gestational hypertension?. BJOG 2008; 115 (05) 607-615
• 124 Hammer F, Stewart PM. Cortisol metabolism in hypertension. Best Pract Res Clin Endocrinol Metab 2006; 20 (03) 337-353
• 125 Kang J, Chang Y, Kim Y, Shin H, Ryu S. Ten-second heart rate variability, its changes over time, and the development of hypertension. Hypertension 2022; 79 (06) 1308-1318
• 126 Kivioja A, Toivonen E, Tyrmi J. et al. Increased risk of preeclampsia in women with a genetic predisposition to elevated blood pressure. Hypertension 2022; 79 (09) 2008-2015
• 127 Nilsson E, Salonen Ros H, Cnattingius S, Lichtenstein P. The importance of genetic and environmental effects for pre-eclampsia and gestational hypertension: a family study. BJOG 2004; 111 (03) 200-206
• 128 Kiecolt-Glaser JK. Stress, food, and inflammation: psychoneuroimmunology and nutrition at the cutting edge. Psychosom Med 2010; 72 (04) 365-369
• 129 Dolsen EA, Crosswell AD, Prather AA. Links between stress, sleep, and inflammation: are there sex differences?. Curr Psychiatry Rep 2019; 21 (02) 8
• 130 Ramakrishnan U. Nutrition and low birth weight: from research to practice. Am J Clin Nutr 2004; 79 (01) 17-21
• 131 Soto E, Bahado-Singh R. Fetal abnormal growth associated with substance abuse. Clin Obstet Gynecol 2013; 56 (01) 142-153
• 132 Bovin MJ, Marx BP. The problem with overreliance on the PCL–5 as a measure of PTSD diagnostic status. Clin Psychol Sci Pract 2023; 30 (01) 122-125
• 133 Powers A, Woods-Jaeger B, Stevens JS. et al. Trauma, psychiatric disorders, and treatment history among pregnant African American women. Psychol Trauma 2020; 12 (02) 138-146
• 134 Weathers FW, Keane TM, Davidson JR. Clinician-administered PTSD scale: a review of the first ten years of research. Depress Anxiety 2001; 13 (03) 132-156
• 135 Su S, Jimenez MP, Roberts CT, Loucks EB. The role of adverse childhood experiences in cardiovascular disease risk: a review with emphasis on plausible mechanisms. Curr Cardiol Rep 2015; 17 (10) 88
• 136 Huffhines L, Noser A, Patton SR. The link between adverse childhood experiences and diabetes. Curr Diab Rep 2016; 16 (06) 54
• 137 Chandan JS, Okoth K, Gokhale KM, Bandyopadhyay S, Taylor J, Nirantharakumar K. Increased cardiometabolic and mortality risk following childhood maltreatment in the United Kingdom. J Am Heart Assoc 2020; 9 (10) e015855
• 138 Goncalves Soares A, Zimmerman A, Zammit S, Karl A, Halligan SL, Fraser A. Abuse in childhood and cardiometabolic health in early adulthood: evidence from the Avon longitudinal study of parents and children. J Am Heart Assoc 2021; 10 (24) e021701
• 139 Gluck RL, Hartzell GE, Dixon HD. et al. Trauma exposure and stress-related disorders in a large, urban, predominantly African-American, female sample. Arch Women Ment Health 2021; 24 (06) 893-901
• 140 Records, Wilson BL, Dyer JM. et al Exploring the Psychosocial Predictors of Gestational Diabetes and Birth Weight. J Obstet Gynecol Neonatal Nurs 2015; 44 (06) 760-771