Biological and Behavioral Pathways from Prenatal Depression to Offspring Cardiometabolic Risk: Testing the Developmental Origins of Health and Disease Hypothesis

Abstract

Given prior literature focused on the Developmental Origins of Health and Disease framework, there is strong rationale to hypothesize that reducing depression in the prenatal period will cause improvements in offspring cardiometabolic health. The current review outlines evidence that prenatal depression is associated with offspring cardiometabolic risk and health behaviors. We review evidence of these associations in humans and in non-human animals at multiple developmental periods, from the prenatal period (maternal preeclampsia, gestational diabetes), neonatal period (e.g., preterm birth, small size at birth), infancy (rapid weight gain), childhood and adolescence (high blood pressure, impaired glucose-insulin homeostasis, unfavorable lipid profiles, abdominal obesity), and into adulthood (diabetes, cardiovascular disease). In addition to these cardiometabolic outcomes, we focus on health behaviors as outcomes associated with cardiometabolic risk, such as child eating behaviors, diet, physical activity, and sleep health. Our review focuses on both child behaviors (e.g., emotional eating, preference for highly palatable foods, short sleep duration) and parenting behaviors (e.g., pressuring child to eat, modeling of health behaviors). These changes in health behaviors may be detected before changes to cardiometabolic outcomes, which may allow for early identification of and prevention for children at risk for poor cardiometabolic outcomes in adulthood. We also discuss the methods of the ongoing Care Project, which is a randomized clinical trial to test whether reducing prenatal maternal depression improves offspring’s cardiometabolic health and health behaviors in preschool. The goal for this review and the Care Project are to inform future research, interventions, and policies that support prenatal mental health and the cardiometabolic health of offspring.

Cardiovascular disease (CVD) is the leading cause of death worldwide (Nowbar et al., 2019). Robust epidemiological evidence consistent with the Developmental Origins of Health and Disease (DOHaD) framework indicates that the origins of CVD begin in the fetal period, and yet the processes by which the prenatal environment contributes to poor cardiometabolic health are poorly understood. We focus on maternal depression during the prenatal period as a plausible exposure contributing to the fetal origins of CVD because 1) approximately 17% of pregnant individuals meet criteria for a Major Depressive Disorder (MDD) diagnosis (Underwood et al., 2016), and 2) prenatal depression is associated with negative consequences for child development (Davis et al., 2018). There is a need to study maternal prenatal depression as a potential cause of offspring biological and behavioral alterations that may increase risk for offspring CVD during their lifespan.

The DOHaD framework posits that prenatal and preconception experiences and exposures, including nutrition, toxins, and maternal experiences such as psychosocial stress and depression, are biologically embedded in the fetus (through “fetal programming”) to increase risk for a number of disorders, including CVD, diabetes, and psychopathology (Barker, 1998; Gillman, 2005; Gluckman & Hanson, 2006). There are clearly multiple biological and behavioral pathways by which fetal experiences lead to offspring risk for adult disease. Plausible biological pathways include but are not limited to maternal, paternal, and fetal stress system regulation, inflammatory pathways, epigenetic processes, metabolic hormone regulation, the microbiome, fetal brain development, and placental physiology. These biological pathways may also lead to changes in offspring behaviors, such as alterations in sleep, eating behaviors, dietary preferences, and physical activity, which have implications for adult disease risk. Future research is needed to identify both biological and behavioral pathways by which prenatal experiences and exposures contribute to lifespan offspring health and disease.

The Current Review

The current review describes existing evidence for biological and behavioral pathways between prenatal maternal depression and offspring cardiometabolic risk. CVD refers to several diseases of the heart and blood vessels, while cardiometabolic risk refers to risk factors for developing later CVD or diabetes (e.g., hypertension, smoking, abdominal obesity, inflammation; Chatterjee et al., 2012). We first frame research on the association between prenatal maternal depression and offspring cardiometabolic risk within the social determinants of health framework, which incorporates the structural, social, and environmental determinants of maternal and offspring health. Within this section, we feature a discussion of the emerging literature on weight-based stigma, a social factor that may contribute to the association between prenatal depression and offspring cardiometabolic risk.

We then overview evidence that prenatal maternal depression contributes to birth outcomes (preterm birth and low birth weight), which in turn are robust predictors of adult CVD (Barker, 1998; Barker et al., 2002; Gluckman et al., 2005). These studies make a compelling case that prenatal depression contributes to CVD. However, it is unlikely that birth outcomes such as preterm birth and low birth weight are themselves the cause of later CVD; it is more likely that prenatal physiological and behavioral alterations that cause preterm birth and low birthweight also cause later CVD (Harding, 2001). Thus, there is a need to explore plausible pathways by which prenatal depression may influence fetal physiological systems that contribute to subsequent CVD (see Figure 1; Gluckman et al., 2008; Harding, 2001). To address this gap, we next overview the few prospective studies that directly test links between prenatal maternal depression and offspring CVD risk.

Figure 1.

Model of fetal programming of offspring cardiometabolic risk following prenatal depression. Note: Birth outcomes (preterm delivery, small size at birth, birth complications) are robustly associated with prenatal depression and poorer offspring cardiometabolic health. However, birth outcomes are likely not a cause of poorer offspring health. It is more likely that fetal programming mechanisms link prenatal depression to both poorer birth outcomes and offspring cardiometabolic health. Thickness of lines corresponds with the robustness of current evidence for the association (thicker = stronger current evidence).

We next probe mechanisms by which prenatal maternal depression may contribute to CVD in the offspring focusing on biological and behavioral processes that are both affected by prenatal depression and are known risk factors for CVD (Figure 2). In this section, we first present evidence for prenatal health complications that can follow or co-occur with prenatal depression. Second, we present evidence for potential biological pathways that are associated with prenatal maternal depression and offspring cardiometabolic risk. Third, we cover evidence for behavioral pathways, including maternal behaviors during and after pregnancy and postnatal behaviors of their offspring. In this review, we prioritize studies that focus on maternal depression as a predictor; however, evidence linking maternal depression to certain biological and behavioral pathways is less robust than for other pathways. For these suggestive pathways where there are fewer studies directly evaluating prenatal maternal depression, we incorporate research on related prenatal perturbations such as prenatal stress to argue that a specific pathway should be investigated in future research. After the review of the literature, we then offer future directions for research in the field, which includes using randomized clinical trials (RCTs) to experimentally test whether reducing prenatal depression reduces offspring cardiometabolic risk. Finally, we briefly outline the Care Project (Davis et al., 2018), an ongoing study which provides an experimental test of the DOHaD hypothesis.

Figure 2.

Conceptual model with mediators between prenatal depression and offspring cardiometabolic health.

Social Determinants of Health

The social determinants of health include factors from five domains: economic stability, education access/quality, healthcare access/quality, neighborhood and the built environment, and the social and community context (Giroir, 2021). There is extensive evidence that these social and structural factors such as socioeconomic status, the built environment, community support, and high-quality healthcare and education are strongly linked to both prenatal maternal depression and adult CVD (Allen et al., 2014; Jilani et al., 2021), as well as intermediary processes such as birth outcomes (Liu & Glynn, 2022). As a result, the consideration of pathways linking prenatal depression with offspring CVD is incomplete without the lens of the social determinants of health that contribute to both the predictor (prenatal depression) and the outcome (CVD). Specifically, researchers and policymakers must consider that access to resources and supports may not exist in certain environments. In addition, structural barriers and social factors may increase experiences of discrimination (e.g., pregnancy-related, racial/ethnic, or weight-or gender-based discrimination), which has implications for both mental and physical health (e.g., Anderson, 2013).

A growing literature has examined the contributions of weight-based stigma on the health of individuals with overweight and obesity, though less research has examined potential impacts of weight-based stigma experienced during pregnancy on offspring health specifically. Weight-based stigma and discrimination has been steadily increasing over time in the United States (Andreyeva et al., 2008). Living in a larger body in an environment with growing weight stigma may have its own implications for maternal and offspring cardiometabolic health, in addition to documented associations between experiencing weight stigma and poorer mental health (Incollingo Rodriguez & Nagpal, 2021). For example, pregnant individuals with higher BMI pre-pregnancy or who gain excessive weight across pregnancy are more likely to have higher weight bias internalization compared to those with lower BMI or weight gain (Nagpal et al., 2022). Weight bias internalization has been associated with poorer adult mental health (Pearl & Puhl, 2018) and greater adult cardiometabolic risk (Pearl et al., 2017), which may be a psychosocial pathway by which higher weight may lead to poorer health outcomes for pregnant individuals and their offspring. Weight-based stigma in healthcare settings is a common experience for pregnant individuals (Incollingo Rodriguez et al., 2020). Healthcare providers with explicit or implicit biases may provide substandard care or create a hostile environment where the pregnant individual does not return or needs to switch providers for routine prenatal care, which may have health consequences for both the mother and the fetus (Incollingo Rodriguez et al., 2020). Holding multiple minoritized identities may also place individuals at greater risk for weight-based stigma and discrimination and poor health outcomes (Incollingo Rodriguez & Nagpal, 2021). Future research is needed to understand the role of weight-based stigma and other types of discrimination in the association between prenatal maternal depression and offspring cardiometabolic risk.

Maternal Prenatal Depression

Maternal prenatal depression¹ is one of the most common and costly prenatal complications with substantial contributions to morbidity (Howard & Khalifeh, 2020). Rates of depression are highest among populations experiencing stressors including socioeconomic disadvantage, racism, and trauma (Lancaster et al., 2010; Noroña-Zhou et al., 2022). Robust evidence links prenatal maternal depression to birth outcomes (Diego et al., 2009; Grigoriadis et al., 2013; Grote et al., 2010; Jarde et al., 2016), offspring cognitive and emotional function (Davis et al., 2004, 2018), and offspring psychopathology (Davis et al., 2018; Davis & Sandman, 2012). Importantly, prenatal maternal symptoms of distress predict later infant and child psychopathology and risk mechanisms (e.g., negative emotionality, altered stress physiology, low cognitive control) even when maternal depressive symptoms are subclinical and below diagnostic categorical thresholds (Davis et al., 2018; O’Connor et al., 2014). As a result, both clinical and subclinical levels of depression should be probed in studies to better understand associations with offspring outcomes.

Prenatal Depressive Symptoms and Poor Birth Outcomes

Recent meta-analytic evidence highlights that greater prenatal maternal depressive symptoms are strongly linked to poor birth outcomes, including premature delivery and low birthweight (Diego et al., 2009; Dunkel Schetter & Tanner, 2012; Grigoriadis et al., 2013; Grote et al., 2010; Jarde et al., 2016). These poor birth outcomes in turn robustly predict childhood obesity (Gluckman et al., 2005), higher blood pressure (Van Dijk et al., 2012a), and lower insulin sensitivity (Veening et al., 2002), as well as adult CVD, diabetes, and hypertension (Barker et al., 2002; Gluckman et al., 2005). Preterm birth and low birthweight are associated with lasting changes in metabolism and behavior that influence child cardiometabolic health (Barker, 1998; Barker et al., 2002; Gluckman et al., 2005; Gluckman & Hanson, 2006). Young adults born preterm have higher systolic blood pressure, pulse pressure, systolic and diastolic blood pressure variability, and heart rate, suggesting that preterm birth is an indicator of later cardiometabolic risk (Kerkhof et al., 2012). While these studies provide suggestive evidence that prenatal maternal depression may contribute to CVD, prospective work is needed to directly probe the link between prenatal depression and cardiometabolic health and underlying mechanisms.

Prenatal Depressive Symptoms and Offspring Cardiometabolic Risk: Prospective Evidence

Greater maternal prenatal depressive symptoms are associated with poorer offspring cardiometabolic health in prospective observational studies, including obesity (Benton et al., 2015; Milgrom et al., 2012; Vehmeijer et al., 2019) and central adiposity (Ertel et al., 2010) in early childhood. Prenatal depression predicts greater child central adiposity and smaller overall body size in children at 3 years of age, when compared to offspring of mothers without depression (Ertel et al., 2010). Although there are relatively few studies measuring depression, prospective studies of stress and stress physiology similarly support links between prenatal maternal distress and offspring cardiometabolic risk. For example, prenatal maternal stress-responsive hormones, which are heightened in response to depression, are associated with rapid infant weight gain, a predictor of later obesity (Stout et al., 2015). Greater psychosocial stress during pregnancy, which also contributes to adverse birth outcomes, is associated with higher systolic and diastolic blood pressure at 5–7 years (Van Dijk et al., 2012a). Animal studies show that experimentally-induced prenatal stress causes higher offspring weight, impaired glycemic control, and greater adiposity, especially when offspring are exposed to a high-calorie diet (reviewed in Entringer, 2013). However, the association between prenatal depression and offspring cardiometabolic health has not been tested experimentally in humans.

Prenatal Medical Complications

Prenatal depression could lead to CVD by increasing risk for other prenatal medical problems such as gestational hypertension, preeclampsia, and gestational diabetes. These conditions could be mediators of the association between prenatal depression and offspring cardiometabolic risk, with the onset of the conditions following the onset of depression. These conditions may also precede prenatal depression, as managing illness during pregnancy may have negative impacts on mental health. Similar to prenatal medical conditions, prenatal depression is often disproportionately experienced by those with lower socioeconomic status and/or who identify as a member of a racially or ethnically marginalized group (Goyal et al., 2010; Mukherjee et al., 2016; Noroña-Zhou et al., 2022). As a result, depression often co-occurs with higher prenatal stress and in the context of racism, poverty, and inadequate prenatal medical care. These structural factors increasing risk for both prenatal depression and poorer offspring health are in line with the robust literature on the social determinants of health (for review, (Powell-Wiley et al., 2022). Below, we discuss hypertension, preeclampsia, and gestational diabetes as medical conditions that may occur following prenatal depression, which may be mediators of the association between prenatal depression and offspring cardiometabolic risk.

Hypertension and Preeclampsia

Prenatal depression is associated with a greater risk for the maternal hypertensive disorder preeclampsia (Hu et al., 2015; Kurki et al., 2000). Several physiological risk factors for both depression and preeclampsia (e.g., inflammation, oxidative stress, reduced endothelial and vascular function) could be associated with both disorders. Preeclampsia is associated with higher BMI and higher systolic and diastolic blood pressure in offspring in childhood and adolescence (Davis et al., 2012). As premature delivery is often a method to stop the progression of the disorder, preeclampsia may lead to poorer offspring birth and developmental outcomes through exposure to suboptimal prenatal conditions and early delivery (Backes et al., 2011). Other possible mechanisms co-occurring or following preeclampsia that could have implications for the fetus include placental insufficiency, in utero insults, or fetal growth restriction (Davis et al., 2012). As a result, prenatal depression may impact offspring cardiometabolic risk by increasing risk for prenatal maternal hypertension and preeclampsia, which in turn have consequences for fetal maturation.

Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM; diabetes diagnosed for the first time in pregnancy) is more likely to occur in pregnant individuals with depression, and subsequent GDM is more common among individuals diagnosed with depression in the first trimester (Morrison et al., 2016). There is a modest direct association between depressive symptoms in early pregnancy and greater risk of incident GDM, with a stronger association for non-obese women (Hinkle et al., 2016). GDM is associated with greater risk of obstetric complications as well as abnormal glucose tolerance, greater BMI, and higher blood pressure in the offspring during childhood (Tam et al., 2017). As a result, prenatal depression could increase risk for co-occurring or subsequent GDM during pregnancy, which could program offspring metabolic risk. The association between diabetes and depression is likely bidirectional. Women who had both prenatal depression and GDM were 7.38 times as likely to have postnatal depression compared to individuals with neither disorder, though individuals with only GDM had no increased postnatal depression risk (Shuffrey et al., 2023). These findings suggest that the co-occurrence of prenatal depression and GDM could operate jointly to increase risk of postnatal depression, which could influence offspring developmental risk through postnatal depression pathways described below. Overall, research suggests that prenatal depression may increase risk for GDM, which could be a pathway by which prenatal depression may increase offspring cardiometabolic risk.

Evidence for Biological and Behavioral Pathways

Biological Pathways

This section reviews potential pre- and postnatal biological pathways by which prenatal maternal depression may influence offspring cardiometabolic risk, including: 1) hypothalamic-pituitary-adrenal (HPA) axis, 2) immune system, 3) epigenetics, 4) brain development, 5) metabolism, and 6) microbiome. These plausible biological pathways were chosen because there was both evidence linking prenatal depression to alterations in that system and evidence that alterations in that system are associated with cardiometabolic risk. We acknowledge that there may be other important biological processes involved in this association that are not reviewed here (e.g., altered mitochondrial function; Zitkovsky et al., 2021). We also acknowledge that although there are established genetic risk factors for both depression and CVD that underlie a significant proportion of the variance in intergenerational transmission of health risk. In this review, we focus on biological pathways that may be modified by prenatal maternal depression (e.g., epigenetics) rather than stable pathways of risk (e.g., DNA sequence).

Hypothalamic-Pituitary-Adrenal (HPA) Axis

Maternal depression in the prenatal period is a known activator of prenatal stress-responsive hormones such as placental corticotrophin-releasing hormone (CRH) and maternal cortisol (Kassotaki et al., 2021; Peterson et al., 2020; Rich-Edwards et al., 2008). Both placental CRH and maternal cortisol normatively increase across gestation (Mastorakos & Ilias, 2003) and are implicated in fetal development. Prenatal depression can alter these normative trajectories (Kassotaki et al., 2021; Mancuso et al., 2004; Rich-Edwards et al., 2008). One process by which altered levels of placental CRH and cortisol may affect offspring CVD risk is via programming of offspring HPA axis activity (Davis et al., 2011; Irwin et al., 2021). The HPA axis is involved in the regulation of metabolism and appetite (Bouret, 2009; Leal-Cerro et al., 2001), which may indicate a pathway through which prenatal cortisol and placental CRH exposure may impact long-term offspring cardiometabolic health. In addition to alterations to the developing fetal HPA axis, CRH and cortisol may directly impact offspring fat storage and insulin production. CRH is an important regulator of adipocyte function (Grammatopoulos, 2008), and cortisol is linked to offspring fat storage and insulin production (Campbell et al., 2011; Schwitzgebel et al., 2009).

As discussed in a recent review (Deer, Su, et al., 2023), prenatal stress-responsive hormones and subsequent offspring HPA axis activity may have broad effects on offspring cardiometabolic risk factors, including altered growth patterns and health behaviors. Indeed, both placental CRH and cortisol have been linked in both human and non-human animal model studies to markers of cardiometabolic risk such as catch-up growth (Mustoe et al., 2012; Stout et al., 2015), higher BMI and adiposity (Gillman et al., 2006; Hohwü et al., 2015; Kuo et al., 2017; Van Dijk et al., 2012b), and higher blood pressure (Burgueño et al., 2020; de Vries et al., 2007; Rondó et al., 2010). These stress responsive hormones have also been linked to health behaviors related to cardiometabolic risk such as offspring substance use (Rodrigues et al., 2012; Stroud et al., 2014), eating behaviors (Hauser et al., 2007; Schroeder et al., 2017), and infant regulatory behaviors such as sleeping (Räikkönen et al., 2015). These findings suggest a pathway from prenatal maternal depression to offspring cardiometabolic risk through alterations in the maternal and offspring HPA axis. Future research is needed to better understand the roles of the prenatal maternal and fetal HPA axis as well as the role of the offspring HPA axis as pathways from prenatal depression to offspring cardiometabolic risk.

Immune System

Prenatal maternal depression could impact offspring cardiometabolic risk through alterations in the offspring’s immune system and levels of inflammation. Like the HPA axis, the immune system undergoes a myriad of changes over the course of pregnancy (Abu-Raya et al., 2020). Studies in humans and non-human primates both suggest that offspring of pregnancies characterized by high prenatal stress show poorer immune function and greater susceptibility to illnesses (Coe & Lubach, 2000; Coussons-Read, 2013; Stepanikova et al., 2019). Prenatal depression is associated with an elevated maternal inflammatory response to immune challenges with high levels of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) and lower levels of anti-inflammatory cytokine IL-10 (Christian et al., 2009; Coussons-Read et al., 2005). Pregnant women experiencing depression have also shown heightened levels of cytokine macrophage migration inhibitory factor in response to an influenza vaccine in comparison to non-depressed pregnant women (Christian et al., 2010). Heightened inflammatory responses (e.g., higher TNF-a) as well as other immune alterations such as elevated leukocytes, and alterations in the expression of genes involved in the immune response (e.g., Toll-like receptor 4), have been linked in animal studies to poorer birth outcomes (Cadaret et al., 2019; Cappelletti et al., 2020), which are associated with offspring cardiometabolic risk. Inflammatory responses to challenge have also been directly linked to offspring cardiometabolic risk. Non-human animal model research finds that prenatal exposure to an immune challenge and the subsequent inflammatory response (higher IL-6 and TNF-a) resulted in increased body fat percentage and decreased energy expenditure in offspring (Ni et al., 2022).

Several studies have also documented that prenatal depression is associated with greater inflammation in offspring. One study demonstrated that prenatal maternal depression is associated with lower levels of anti-inflammatory cytokine IL-10 in cord blood at birth, suggesting that these altered immune responses are present at the beginning of postnatal life (Hahn et al., 2019). These differences may persist later into development as well. For example, greater depressive symptoms in the third trimester are associated with increased C-reactive protein (CRP) in offspring at 9 years (Dawe et al., 2012). Another study found that depression in the second and third trimesters are associated with higher CRP levels at 25 years of age (Plant et al., 2016). Elevated levels of inflammation are an established risk factor for later CVD (Hansson, 2005). This body of work suggests that a likely pathway by which prenatal depression influences offspring cardiometabolic risk is through increased inflammation.

Epigenetics

Prenatal depression could lead to offspring CVD risk through epigenetic programming in utero. Epigenetics is the modification of gene expression (often via DNA methylation and histone modification), which does not involve changes in the sequence of DNA. A growing body of research has demonstrated associations between prenatal depression and the offspring epigenome through both candidate gene and epigenome-wide association studies. These studies have reported methylation differences in specific genes by depression status, including those for the glucocorticoid receptor (NR3C1), oxytocin receptor (OXTR), and serotonin transport (SLC6A4), among others (though the candidate gene and results vary by study; see Faleschini & Cardenas, 2021, for review). Epigenome-wide association studies are fewer in number and, although some of these analyses have identified differential methylation by prenatal depression status, results often do not replicate in other cohorts (Faleschini & Cardenas, 2021). Though not specific to depression, one study demonstrated that epigenetic alterations mediate the association between prenatal stress and offspring adiposity at 13.5 years. Within offspring of people exposed to the 1998 Quebec ice storm during pregnancy, those whose parents had experienced more severe stress during pregnancy had higher central adiposity and BMI at age 13.5 years (Cao-Lei et al., 2015). These changes were mediated by methylation of genes related to Type-2 diabetes mellitus (Cao-Lei et al., 2015). It is possible that depression could create similar alterations in the offspring epigenome that lead to greater cardiometabolic risk. A robust literature exists on epigenetic regulation related to CVD, including preclinical studies targeting epigenetic changes to treat CVD (Shi et al., 2022). However, the prenatal depression-epigenetics and CVD-epigenetics literatures are largely separate and would benefit from integration given associations between prenatal depression and offspring cardiometabolic health. Given documented epigenetic alterations following prenatal depression and stress, and research on the epigenetic alterations associated with CVD, epigenetic alterations could mediate associations between prenatal depression and offspring cardiometabolic outcomes. There is likely heterogeneity in depression presentation, cardiometabolic risk profiles, and comorbid disorders (e.g., anxiety, post-traumatic stress) that need to be better understood when interpreting epigenetic alterations. However, current research is suggestive that epigenetic alterations may mediate the association between prenatal depression and offspring cardiometabolic risk.

Brain Development: Structure and Function

Prenatal maternal mental health is linked to alterations in offspring structural and functional brain development (Demers et al., 2021). Greater prenatal maternal depressive symptoms are associated with decreased offspring cortical thickness in frontal and middle temporal regions during childhood, even after adjusting for postnatal depressive symptoms (Lebel et al., 2016; Sandman et al., 2015). Altered brain maturation could have downstream behavioral and emotional consequences. The frontal and temporal regions associated with prenatal depression underlie executive functioning abilities, and impaired offspring executive function is associated with prenatal depression (Power et al., 2021). Impaired executive functioning, and problems with inhibition in particular, have been associated with greater cardiometabolic risk in children (Deer, Doom, et al., 2023; Reinert et al., 2013). Similarly, prenatal depression is associated with offspring negative emotionality (Davis et al., 2018), and elevated amygdala responses to negatively valenced stimuli in 6–9-year-olds (van der Knaap et al., 2018). Difficulties in self-regulation including regulating negative emotions in childhood are associated with greater cardiometabolic risk (Appleton & Kubzansky, 2014; Deer, Doom, et al., 2023). Growing neurobiological research suggests that neural circuits for both negative emotion and cardiometabolic risk may be overlapping (Kraynak et al., 2018). This body of research suggests that impaired executive functioning and greater negative emotionality, and the neural circuits supporting these functions, may be pathways to greater cardiometabolic risk following prenatal maternal depression. Changes in offspring brain structure, function, and metabolism following prenatal depression are likely pathways to poorer health behaviors and greater offspring cardiometabolic risk.

Metabolism

Prenatal depression has been associated with clinical markers of metabolic function (e.g., blood pressure, adiposity) as described above in the section on prospective evidence between prenatal depression and offspring cardiometabolic outcomes. As a result, this section focuses on preclinical markers of metabolic function associated with prenatal depression (e.g., leptin, maternal metabolome, breastmilk composition). Prenatal depression has been associated with shifts in offspring metabolic hormones that could confer risk for later CVD. Prenatal maternal mental health problems are associated with lower infant cord blood leptin but not adiponectin levels (Scott & Manczak, 2021), and lower cord blood leptin is associated with smaller size at birth, greater weight gain from 0–6 months of age, and higher BMI at age 3 years (Mantzoros et al., 2009). Less is known about whether shifts in the maternal and offspring metabolome following prenatal depression could be a mechanism for greater offspring cardiometabolic risk. The metabolome is the collection of metabolites that cells produce during metabolism, and the study of metabolomics measures these metabolites to better understand cellular and physiological function. There is evidence that prenatal depression is associated with shifts in the maternal plasma metabolome, including higher levels of three triacylgylcerol metabolites and lower levels of betaine, citrulline, C5 carnitine, and C5:1 carnitine (Mitro et al., 2020). More research is needed to understand the implications of these shifts in the maternal plasma metabolome. These changes in the maternal metabolome may provide insight into the pathophysiology of prenatal depression and could have implications for the developing fetus.

An emerging body of work on lactation and breastmilk composition suggests that prenatal psychological distress (depression and anxiety) are associated with alterations in the milk metabolome, including greater concentration of short-chain fatty acids, caprate, and hypoxanthine (Kortesniemi et al., 2021). Maternal psychological distress may impair oxytocin release, which can negatively affect milk ejection and eventually decreased milk production due to incomplete emptying of the breast (Nagel et al., 2022). In addition, maternal psychological distress may lead to greater levels of cortisol and lower insulin sensitivity, which are both related to decreased milk production (Nagel et al., 2022). Future work is needed to better understand how prenatal and early postnatal depression may affect lactation and milk composition to test whether these physiological changes may be another pathway by which prenatal depression may influence offspring cardiometabolic risk (Neville et al., 2023).

More work has been conducted with prenatal stress, which often co-occurs with depression, and its relation to offspring metabolic outcomes. Non-human animal studies show that experimentally-induced prenatal stress causes higher offspring weight, impaired glycemic control, and greater adiposity, especially when offspring are exposed to a high-calorie diet (Entringer, 2013). Work that examines prenatal stressors in humans finds that stressors during pregnancy are associated with greater offspring insulin resistance in adulthood, suggesting possible prenatal programming of glucose-insulin metabolic function (Entringer et al., 2008). However, in one notable study, prenatal stress was not associated with offspring glucose metabolism and insulin resistance at 5–6 years (Van Dijk et al., 2014); thus, this association may emerge later in life. Indeed, the 1998 Quebec ice storm study found that greater prenatal stress was associated with greater offspring insulin secretion in adolescence (Dancause et al., 2013). Studying alterations in metabolic function using tools such as metabolomics and tracking of glucose-insulin metabolic function longitudinally following prenatal depression exposure and understanding whether any metabolic alterations subsequently predict cardiometabolic risk will be important future directions. Overall, this body of work is suggestive that several preclinical metabolic markers and processes are likely mediators of the association between prenatal depression and offspring cardiometabolic risk.

Microbiome

Prenatal depression is associated with shifts in the infant gut microbiome for infants who are either fully- or partially formula-fed (Rodriguez et al., 2021). Gut immunity (secretory Immunoglobulin A) may also be altered in infants following prenatal maternal depression independent of feeding status. Beneficial microbes (e.g., members of bifidobacteria) are reduced in infant offspring of mothers with higher prenatal depressive symptoms (Galley et al., 2023). In the human prenatal stress literature, shifts in the infant microbiome toward a microbiota composition known to contain pathogens (related to Serratia, Escherichia, and Enterobacter) has been demonstrated following high maternal prenatal stress (Zijlmans et al., 2015). This microbiota composition was associated with greater infant allergic reactions and gastrointestinal symptoms (Zijlmans et al., 2015), suggesting potential health implications. Growing research suggests that the microbiome may have implications for cardiometabolic health. Composition of the gut microbiome differs between normal weight children and children with obesity (Maya-Lucas et al., 2019). There is evidence that the gut microbiome is shaped in infancy and childhood, with potential long-term implications for cardiometabolic risk throughout the lifespan (Mohammadkhah et al., 2018). The microbiome is an important potential mediator in the prenatal depression to offspring cardiometabolic risk association that should be investigated in future years.

Behavioral Pathways

Prenatal Maternal Health Behaviors

In this section, we review potential prenatal health behaviors that are documented to be impacted by prenatal depression and that also may predict offspring cardiometabolic health. This section reviews selected literature on prenatal maternal health behaviors, including 1) prenatal diet, 2) prenatal physical activity, 3) prenatal sleep, and 4) prenatal substance use. Similar to the biological pathways section, these behaviors were chosen because there was both evidence linking prenatal depression to the behaviors and evidence that these behaviors are associated with offspring cardiometabolic risk.

Prenatal Diet

Greater prenatal depressive symptoms are associated with higher maternal consumption of processed food and lower consumption of healthy nutrition (e.g., vegetables, fish, non-meat protein) (Barker et al., 2013), which could affect the nutrients received and flavors the fetus is exposed to in utero and alter subsequent food intake in offspring (Lesage et al., 2004; Paternain et al., 2012). There is evidence that flavors ingested by the mother are transmitted to offspring through amniotic fluid (Mennella, 2014) and that fetuses are differentially responsive to unique flavors (specifically sweet and bitter flavors) in utero (Ustun et al., 2022). Foods ingested during pregnancy or during the lactation period are more likely to be accepted by infants around 6 months of age (Mennella, 2014), suggesting that diet of the mother during pregnancy may lay the foundation for the child’s dietary preferences.

Prenatal depression is associated with poorer dietary quality during pregnancy (Avalos et al., 2020; Baskin et al., 2015), including greater consumption of calories from added sugars, solid fats, and alcohol, lower consumption of fruit, and lower consumption of greens and beans compared to individuals without prenatal depression (Avalos et al., 2020). Robust evidence, including studies of offspring following the Dutch Hunger Winter of 1944–1945, suggests that undernutrition during early pregnancy is associated with greater cardiometabolic risk in offspring (Roseboom et al., 2006). Undernutrition includes not having enough to eat or not eating or absorbing enough necessary macronutrients and micronutrients from one’s diet, which is consistently associated with offspring cardiometabolic health (Gluckman et al., 2008; Harding, 2001). Socio-contextual factors, including socioeconomic status, strongly shape food access which changes the availability of foods available to pregnant individuals. As a result, these social and structural factors almost certainly influence both maternal mental health and dietary quality during pregnancy. Given growing research that prenatal depression is associated with prenatal dietary intake, and the extensive evidence that prenatal undernutrition is associated with offspring cardiometabolic risk, prenatal dietary quality is a likely pathway between prenatal depression and offspring cardiometabolic risk.

Prenatal Physical Activity

There is cross-sectional evidence of associations between greater prenatal depression and lower physical activity (Demissie et al., 2011). However, most research in this area investigates lower physical activity during pregnancy as a precursor for later depression or uses physical activity interventions during the perinatal period to decrease later depression risk. Indeed, a few recent systematic reviews have documented that physical activity during pregnancy may be effective in reducing depression symptoms (Eustis et al., 2019; Kołomańska et al., 2019) and that physical activity may even play a role in preventing postnatal depression (Nakamura et al., 2019). Of course, depression likely also influences the amount of physical activity for the pregnant individual. It is possible pregnant individuals who engage in physical activity in pregnancy may be less likely to have prenatal and/or postnatal depression. These individuals who are more active during pregnancy may also engage greater physical activity in the postnatal period, and model that behavior to their child. It is also possible that more physical activity is associated with lower offspring cardiometabolic risk through reduced prenatal medical complications. Prenatal maternal physical activity is associated with reduced risk of GDM, gestational hypertension, preeclampsia, and excessive gestational weight gain (DiPietro et al., 2019; Ribeiro et al., 2022). Further, higher physical activity during pregnancy is associated with lower risk of preterm birth and being small for gestational age (Chen et al., 2021) and better offspring cardiometabolic health (Chen et al., 2021; Moyer et al., 2016; Nagpal & Mottola, 2020). Possible mechanisms could include reducing incidence of GDM and preterm birth, changing prenatal physiological regulation, and continued physical activity in the postnatal period that is modeled to the child. Existing research is suggestive that prenatal depression could lead to poorer offspring cardiometabolic health through a pathway of decreased physical activity during pregnancy.

Prenatal Sleep

Given known links between depression and sleep (Fang et al., 2019), sleep is a highly plausible pathway by which prenatal depression may impact offspring cardiometabolic risk. A recent meta-analysis demonstrates that prenatal depression was associated with both lower maternal sleep duration and lower sleep quality (moderate effect size; (Pauley et al., 2020). While few studies have linked prenatal sleep to offspring CVD, poor prenatal sleep is consistently associated with poorer birth outcomes (Okun et al., 2012), and a few studies have linked prenatal maternal sleep to the programming of offspring disease (Chang et al., 2010; Moreno-Fernandez et al., 2020). These preliminary human studies are bolstered by experimental preclinical work showing that in rodents, prenatal sleep restriction causes higher blood pressure and renal abnormalities in offspring (Argeri et al., 2016; Thomal et al., 2010), which could have implications for later cardiometabolic function. This body of work suggests that poor prenatal sleep may be a pathway by which prenatal depression leads to greater offspring cardiometabolic risk.

Prenatal Substance Use

The links between prenatal depression and prenatal substance use, as well as between prenatal substance use and offspring cardiometabolic risk are well-studied. Thus, we will briefly overview relevant papers here. Prenatal depression is associated with greater substance use during pregnancy, including nicotine, alcohol, caffeine, and illicit drugs (e.g., marijuana, methamphetamine; Field et al., 2007; Orr et al., 2012; Pentecost et al., 2021). Further, high rates of comorbidity in prenatal substance use and depression have been reported in epidemiological studies (Shen et al., 2020). Substance use, including smoking tobacco (Himes et al., 2013; Oken et al., 2008), alcohol (Sarman, 2018; Weeks et al., 2020), greater caffeine intake (Jin & Qiao, 2021), and illicit drug use (Cajachagua‐Torres et al., 2022; Zhang et al., 2021) has been associated with poorer offspring outcomes such as low birthweight and higher cardiometabolic risk. As prenatal depression and substance are highly comorbid, substance use could be an additional exposure that may predispose children to higher cardiometabolic risk, though more research is needed to understand temporal associations.

Postnatal Maternal Behaviors

This section reviews postnatal maternal behaviors that have been associated with prenatal depression and with child cardiometabolic health. We include literature on 1) parental feeding behaviors, 2) parental modeling of health behaviors to their child, and 3) parenting and the attachment relationship. As in previous sections, we chose these behaviors because there was both literature linking prenatal maternal depression to these postnatal maternal behaviors and literature demonstrating that these behaviors are associated with cardiometabolic risk.

Maternal Feeding Behaviors

Prenatal depressive symptoms may affect offspring diet through parental feeding behaviors toward the child, including breastfeeding, pressuring children to eat, restricting food, or choosing what foods to serve children. There are few studies on prenatal depressive symptoms specifically predicting feeding behaviors, as most of the literature on feeding is with mothers with high concurrent depressive symptoms. While it is possible that prenatal depressive symptoms may have an independent association with maternal feeding behaviors, it is also likely that prenatal maternal depression may influence feeding via concurrent maternal depressive symptoms.

Mothers with higher postnatal depressive symptoms are less likely to ever breastfeed (Neville et al., 2023), more likely to discontinue breastfeeding early, and more likely to report difficulties with breastfeeding (Dennis & McQueen, 2007; McLearn et al., 2006). A large meta-analysis demonstrated that breastfeeding is directly related to lower child BMI and obesity risk (Yan et al., 2014). However, results of interventions that increase breastfeeding to improve offspring health are mixed (Kramer et al., 2007). It is possible that behaviors that reduce the likelihood of breastfeeding could lead to a higher risk of child obesity. Breastfeeding may also impact child eating behaviors. Toddlers of mothers who breastfeed for a longer duration (at least 6 weeks) show increased satiety responsiveness (Brown & Lee, 2012). This finding suggests that longer breastfeeding duration could positively influence child satiety responsiveness, which has been associated with lower child BMI percentile and waist circumference (Carnell & Wardle, 2008).

Mothers with high postnatal depressive symptoms are more likely to exhibit feeding behaviors that increase risk for obesity, including pressuring their child to eat and being more demanding in encouraging or discouraging children’s eating compared to mothers with low depressive symptoms (Goulding et al., 2014). Mothers with high postnatal depressive symptoms show more forceful, indulgent, and uninvolved feeding styles (Hurley et al., 2008), exhibit greater pressure to eat, and for non-overweight (BMI < 25) mothers, show more restriction of their child’s eating (Francis et al., 2001). Mothers with high postnatal depressive symptoms are more likely to use more age-inappropriate feeding practices (e.g., feeding solids or juice by 3 months of age; (Thompson & Bentley, 2013), use food as a reward, and to have less optimal mealtime practices and routines (Lindsay et al., 2017). In addition, mothers with high depressive symptoms were more likely to have non-responsive feeding practices that were uninvolved (e.g., not being with children during meals, allowing children to watch TV during meals) or permissive (greater child choice in snacking, lower level of maternal control over eating routines; Lindsay et al., 2017). These effects may operate longitudinally, as higher maternal depressive symptoms at 4 months postpartum are associated with greater pressure, restriction, instrumental, and emotional feeding at age 2 years (Mallan et al., 2015). Mothers with high postnatal depressive symptoms are also more likely to feed their toddlers fried foods and more servings of salty snacks (Wasser et al., 2013). More research is needed to understand the unique role of prenatal depressive symptoms compared to postnatal depressive symptoms in feeding behavior pathways, though feeding behaviors are likely one pathway from maternal depression to offspring cardiometabolic risk.

Maternal Modeling of Health Behaviors to the Child

Depression in adulthood has been robustly associated with poorer diet and eating behaviors (Skinner et al., 2012; Whitaker et al., 2014), lower physical activity (McKercher et al., 2009), and poorer sleep (Riemann et al., 2001). Given the importance of modeling for health behaviors, this is a likely pathway by which perinatal maternal depression impacts child cardiometabolic risk. For example, mothers’ own eating behaviors may also be affected by her depressive symptoms, as mothers with high depressive symptoms report higher dietary restraint (Francis et al., 2001), which could be modeled to the child and affect child eating behaviors (Scaglioni et al., 2011). In addition, preschoolers are more likely to try a new food if the caregiver models consumption of that food (Blissett et al., 2016). Similarly, parent emotional eating has been consistently associated with child emotional eating (Carbonneau et al., 2020). In conclusion, prenatal depression, particularly if left untreated into the postnatal period, could lead to poorer health behaviors in the parent that are then modeled to the child, who may be more likely to adopt the parent’s own health behaviors. More research is needed to understand the role of prenatal depressive symptoms in this health behavior modeling pathway.

Parenting and the Attachment Relationship

One mechanism by which prenatal depression may affect child outcomes is through negative effects on postnatal parenting and the attachment relationship between the parent and offspring. Prenatal experiences and hormones influence the maternal brain during the transition to parenthood (Glynn et al., 2016), and it is likely that exposures such as maternal depression affect this process. One study demonstrated that the strongest predictor of lower maternal attachment to their infant 6–8 weeks post-birth was higher depressive symptoms in late pregnancy (Perry et al., 2011). This finding suggests that maternal attachment feelings begin prenatally, and they may be influenced by maternal depression in ways that persist into the postnatal period. A pathway by which prenatal depression may affect later parenting is through continued depressive symptoms into the postpartum period without effective treatment. As parental depression has been associated with harsher, less responsive parenting (Wolford et al., 2019), untreated depression during pregnancy could persist into the postpartum period with implications for the parent-child relationship.

There is evidence that lower attachment or insecure attachment relationships during infancy predict indicators of poorer cardiometabolic health (higher C-reactive protein, higher BMI, more inflammation-based illnesses) from childhood through adulthood (Bernard et al., 2019; Puig et al., 2013). These associations may occur in part through disruptions in stress physiology and immune function following insecure attachment in infancy (Pietromonaco & Powers, 2015). As a result, prenatal maternal depression could negatively affect cardiometabolic health of the developing child through alterations in the attachment relationship, parenting behaviors, child stress physiology, inflammation, and inflammation-based illnesses. More research is needed to better understand specific pathways involving parenting and the attachment relationship, though alterations in these early relationships are a likely mediator between prenatal depression and offspring cardiometabolic risk.

Child Health Behaviors

In the following section, we focus on child health behaviors that have both been associated with prenatal maternal depression and offspring cardiometabolic health. As a result, this section reviews literature on 1) child diet and eating behaviors, 2) child sleep, and 3) child physical activity.

Child Diet and Eating Behaviors

Prenatal depressive symptoms may influence child diet through fetal programming of physiological systems that underlie food preference. As mentioned in the prenatal diet section above, prenatal depression likely influences the parent’s own diet, which changes the foods that the fetus is exposed to in utero. There is evidence that offspring food preferences are programmed by prenatal experiences (Bayol et al., 2007). For example, undernutrition in rats during pregnancy leads to greater offspring preference for high-fat foods (Bellinger et al., 2004). Adult male rats who were offspring of dams exposed to prenatal stress consumed greater saccharin (an artificial sweetener) compared to offspring of dams in non-stress conditions, suggesting prenatal stress may program preference for sweet foods (McGivern et al., 1986). Research in animal models also shows increased food intake in offspring of prenatally stressed dams (Lesage et al., 2004; Paternain et al., 2012).

Most of the work on prenatal influences on offspring diet in humans originates from literature on other prenatal insults rather than depression specifically. For example, a study of preterm infants demonstrated that greater intrauterine growth restriction was associated with lower hedonic responses to sweet taste, which could lead infants to overconsume palatable foods to reach a higher degree of pleasure (Ayres et al., 2012). In addition, smaller size at birth has been associated with lower consumption of fruits in adulthood, which could indicate a poorer adult diet that may predispose individuals to poorer cardiometabolic health (Perälä et al., 2012). As prenatal depression is related to intrauterine growth restriction (Grote et al., 2010), growth restriction, lower hedonic responses to sweet taste, and altered adult diet could be mechanisms by which prenatal depression leads to greater cardiometabolic risk.

In humans, prenatal stress is associated directly with maladaptive eating behaviors in offspring (St‐Hilaire et al., 2015). Work from our group and others establishes that high prenatal depressive symptoms are associated with differences in offspring cognitive, socioemotional, and neurobiological functioning (Davis et al., 2004, 2007, 2018; Doom & Gunnar, 2013) including negative emotionality and self-regulation difficulties (Davis et al., 2018), which are predictors of greater adiposity over time (Francis & Susman, 2009; Pulkki-Råback et al., 2005). Negative emotionality predicts greater emotional overeating and undereating, food tantrums, and poorer diet (higher sweet food and drink intake) (Leung et al., 2014; Messerli-Bürgy et al., 2018; Vollrath et al., 2012). Greater negative mood (depressive symptoms) during childhood also predicts greater preference for sweet foods (Mennella et al., 2010). Self-regulation difficulties may lead to impaired top-down control of food intake (Russell & Russell, 2020). Impairments in child cognitive function and self-regulation are associated with impaired regulation of food intake (Davidson, 2019) and higher BMI (Braungart-Rieker et al., 2016; Deer, Doom, et al., 2023). As a result, alterations in child diet and eating behaviors may be the result of 1) food preferences programmed in utero, 2) greater child negative emotionality, and 3) child self-regulation difficulties. Growing evidence suggests that alterations in early child diet and eating behaviors via food preferences and child emotionality and self-regulation may be pathways from prenatal depression to greater offspring cardiometabolic risk.

Child Sleep

Prenatal depressive symptoms are associated with alterations in child sleep, which may have implications for offspring cardiometabolic health. Prenatal depressive symptoms are associated with more offspring sleep problems in infancy and toddlerhood (O’Connor et al., 2007). A recent cohort study in China demonstrated that mothers with depression and anxiety in pregnancy were more likely to have offspring with shorter sleep duration, longer settling time, and more sleep problems at 30 months of age (Ma et al., 2022). Similarly, a cohort study in New Zealand reported that prenatal depression, but not postnatal or both pre- and postnatal depression, was associated with greater odds of two or more nighttime awakenings for their 2-year-olds (Kim et al., 2020). A Finnish cohort study demonstrated that 3.5-year-old children of women with clinically significant prenatal depressive symptoms had longer sleep latency, more frequent nighttime awakenings, and greater odds of several sleep disorders (Toffol et al., 2019). There is evidence that poorer sleep during childhood is associated with greater risk for obesity as well as alterations in glucose, insulin, blood pressure, and parasympathetic responses to psychological stress (Matthews & Pantesco, 2016). As a result, disruptions in child sleep following prenatal depressive symptoms are a likely pathway to greater offspring cardiometabolic risk.

Child Physical Activity

Offspring physical activity may be affected by prenatal factors. Experimental rodent models of prenatal stress often focus on offspring locomotor activity. In these studies, female offspring of dams exposed to prenatal stress show lower locomotor activity in adulthood (Ordyan & Pivina, 2004). These findings could be due to decreases in motor activity in general or due to depressive-like psychomotor retardation. In rhesus monkeys, offspring of prenatally stressed monkeys are more likely to show lower gross motor/exploratory behaviors (Schneider, 1992) and inactivity in a playroom setting (Clarke et al., 1996). It is unclear how closely these non-human animal motor behaviors map on to child physical activity in humans, though the animal literature suggests that this line of research should be further explored in humans.

In humans, high prenatal depressive symptoms are associated with poorer offspring motor development and lower activity levels (Abrams et al., 1995; Babineau et al., 2022; Field et al., 2006). Cognitive-behavioral therapy to lower depressive symptoms during pregnancy is associated with better offspring motor development at 2 years with medium-to-large effect sizes (Milgrom et al., 2019). More advanced motor development is moderately associated with greater physical activity in children (Iivonen et al., 2013). In addition, high postpartum maternal depressive symptoms are associated with lower offspring physical activity at 4–6 years (Fernald et al., 2008), suggesting possible postnatal pathways as well. Overall, there is experimental animal model and observational human work demonstrating associations between prenatal depressive symptoms and offspring physical activity and motor development. More longitudinal research in humans is needed to better understand whether and how prenatal depression could lead to lower offspring physical activity, and as a result, higher cardiometabolic risk.

Summary of Research

A growing number of prospective studies report links between prenatal maternal depression and offspring CVD risk. The social determinants of health underlie this association as social and structural factors increase risk for both depression and CVD. Plausible biological pathways in the association between prenatal maternal depression and offspring cardiometabolic risk include alterations in the HPA axis, immune system, epigenetics, brain development, metabolism, and the microbiome. Pathways of maternal behavior include parental feeding behaviors, parental modeling of health behaviors to their child, and parenting and the attachment relationship. Postnatal offspring behavioral pathways include child diet and eating behaviors, sleep, and physical activity. The body of research covered in this paper provides strong evidence that the link between prenatal depression and offspring cardiometabolic risk is likely causal via biological and behavioral pathways in both the prenatal and postnatal period.

The vast number of potential biological and behavioral pathways from prenatal maternal depression to offspring cardiometabolic risk is admittedly daunting to researchers, clinicians, and policymakers. We do not want researchers to walk away from reading this article thinking that they must integrate all these pathways into future studies. Instead of being discouraged by the complexity of these pathways, we encourage researchers to choose potential pathways that they can measure using strong methodological and statistical techniques to incrementally increase our understanding of these pathways. We encourage researchers to form interdisciplinary collaborations to integrate biological and behavioral pathways into the same studies. We also encourage researchers, clinicians, and policymakers to follow research on these potential biological and behavioral pathways—even if not their expertise—to better understand potential overlap between pathways that could be targeted in interventions.

Future Directions

There are many important future directions regarding the role of prenatal depression in offspring cardiometabolic health. First, more long-term, prospective studies that start as early as pre-conception, or even during the previous generation, are needed. Although beginning research studies already in the prenatal period is important, there is burgeoning evidence in both non-human animal models and the human literature that pre-conception parental mental health and stress has long-term associations with offspring outcomes (Azizi et al., 2019; Khashan et al., 2009; Moss et al., 2020). Much more work is needed to disentangle how pre-conception mental health may have differential consequences from prenatal or postnatal parental mental health for offspring cardiometabolic risk. Going even further back developmentally, it will be important to understand intergenerational effects, and follow families prospectively through multiple generations. Studying intergenerational effects is particularly important considering that there is evidence of intergenerational transmission of both depression and cardiometabolic risk (Goodman, 2020; Jensen et al., 2021). As highlighted in the current review, there are many different pathways through which prenatal depression might impact offspring cardiometabolic health. As such, it is important that future studies integrate biological and behavioral pathways so that these pathways can be assessed in tandem. There are likely interactive effects across biological and behavioral systems that current studies have not captured.

A large gap in the current literature is a lack of randomized clinical trials (RCTs) with strong interventions to test whether improving prenatal mental health, or the mental health of those trying to conceive, improves offspring cardiometabolic health. These studies would allow for causal inference and better understanding of the mechanisms at play in the association between prenatal depression and offspring cardiometabolic health. Our team has been conducting a RCT that addresses several gaps in the current literature, which we describe next.

Experimentally Testing Fetal Programming Hypotheses: The Care Project

Basic scientific understanding as well as applied translational implications depend on the quality, validity, replicability, and rigor of the empirical corpus of studies that have evaluated the DOHaD hypothesis. The impressive extant body of knowledge supporting the DOHaD hypothesis among humans to date relies entirely upon naturalistic observational studies. Even with the many strong longitudinal studies that have demonstrated temporal precedence of prenatal depressive symptoms predicting later offspring outcomes, these observational studies are inherently limited by the usual caveat of “correlation does not mean causation.” To test causal hypotheses on later offspring outcomes, experimental control is required. Thus, the lack of experimental research design in the human DOHaD hypothesis literature is a limitation in the field. The aim of our ongoing research study, named the Care Project, is to reduce prenatal depression via an RCT of a brief, effective form of Interpersonal Psychotherapy (IPT; MOM-Care; see supplemental materials for more methodological details). We show that brief IPT profoundly reduces prenatal depression during pregnancy (e.g., average 50% decline in self-reported symptom measures over pregnancy, and 5-fold decrease in clinical depression diagnosis, by end of gestation (Hankin et al., 2023) The aims of the original Care Project are to test whether steeper decreases in prenatal depression trajectories reduce early risk for offspring psychopathology across four units of analysis (brain structure/function, physiology, behavior, and parent report; Davis et al., 2018).

Continuing with The Care Project: Reducing Prenatal Depression to Improve Offspring Cardiometabolic Health

The extension of the Care Project builds on the original study by testing whether reducing prenatal depression improves offspring cardiometabolic health and related health behaviors during the preschool period in the same population. As shown in Figure 3, the current study is assessing parental mediators at child age 3 years, including the quality of diet that the parent serves to their child (measured via the Remote Food Photography Method (Martin et al., 2012), parental feeding behaviors (parent-report questionnaire and behavior observation of meal), and parental eating behaviors that may be modeled to the child (parent-report questionnaire). Child mediators at 3 years include child dietary quality (Remote Food Photography Method), child eating behaviors (parent-report, behavioral observation of meal, and emotional eating task), sleep duration, moderate-to-vigorous physical activity, and sedentary behavior (sleep and activity measured via actigraphy, daily diary, and questionnaires). Child health is being assessed via child BMI z-score, waist circumference, and blood pressure at age 3. The outcome assessment at 4 years includes measures of BMI z-score, waist circumference, body fat, blood pressure, and arterial stiffness.

Figure 3.

Conceptual model for the current Care Project data collection, which illustrates pathways by which prenatal maternal depressive symptoms may affect offspring cardiometabolic risk.

Our aims through this longitudinal investigation are to experimentally test pathways in the conceptual model outlined herein. However, we will not be able to test all these pathways in a single study, and we hope the current review provides ideas for future investigations investigating these pathways. The purpose of this review is to highlight the pernicious nature of prenatal depression with its negative effects on both the parent and their offspring. Rather than blame pregnant individuals who experience prenatal depression, this review outlines a research agenda for testing biobehavioral pathways from prenatal depression to offspring CVD, especially increasing the number of RCTs improving maternal mental health. The strong body of literature on the social determinants of health support the implementation and, if effective, dissemination of such interventions to improve health. Finally, if these interventions do improve maternal and offspring health, policymakers and practitioners should support services for pregnant individuals to improve the health of two generations.

Public Significance Statement:

Prenatal depression is pervasive and is associated with poorer offspring development and health. The current review synthesizes evidence of biological and behavioral pathways by which prenatal depression may influence offspring cardiometabolic health. We outline an ongoing study that tests whether reducing prenatal maternal depression improves offspring cardiometabolic health and health behaviors.