Next Article in Journal
Allosteric Inhibition of Neutral Sphingomyelinase 2 (nSMase2) by DPTIP: From Antiflaviviral Activity to Deciphering Its Binding Site through In Silico Studies and Experimental Validation
Next Article in Special Issue
The Significance of COVID-19 Diseases in Lipid Metabolism Pregnancy Women and Newborns
Previous Article in Journal
Destruction of Lysozyme Amyloid Fibrils Induced by Magnetoferritin and Reconstructed Ferritin
Previous Article in Special Issue
Impact of Oxidative Stress on Molecular Mechanisms of Cervical Ripening in Pregnant Women
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Maternal Distress during Pregnancy and the Postpartum Period: Underlying Mechanisms and Child’s Developmental Outcomes—A Narrative Review

Cognitive Neuroscience Department, Research and Development Institute “Life Activities Advancement Institute”, 11000 Belgrade, Serbia
Department of Speech, Language and Hearing Sciences, Institute for Experimental Phonetics and Speech Pathology, 11000 Belgrade, Serbia
Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
Department of Human Pathology, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
Department of Gynecology and Obstetrics, Faculty of Medicine, University of Montenegro, 81000 Podgorica, Montenegro
Clinic of Gynecology and Obstetrics, Clinical Center of Montenegro, 81000 Podgorica, Montenegro
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(22), 13932;
Original submission received: 14 November 2021 / Resubmission received: 20 September 2022 / Revised: 6 November 2022 / Accepted: 7 November 2022 / Published: 11 November 2022


Maternal mental health may be considered a determining factor influencing fetal and child development. An essential factor with potentially negative consequences for a child’s psychophysiological development is the presence of maternal distress during pregnancy and the postpartum period. The review is organized and presented to explore and describe the effects of anxiety, stress, and depression in pregnancy and the postpartum period on adverse child developmental outcomes. The neurobiology of maternal distress and the transmission mechanisms at the molecular level to the fetus and child are noted. In addition, the paper discusses the findings of longitudinal studies in which early child development is monitored concerning the presence of maternal distress in pregnancy and the postpartum period. This topic gained importance in the COVID-19 pandemic context, during which a higher frequency of maternal psychological disorders was observed. The need for further interdisciplinary research on the relationship between maternal mental health and fetal/child development was highlighted, especially on the biological mechanisms underlying the transmission of maternal distress to the (unborn) child, to achieve positive developmental outcomes and improve maternal and child well-being.

1. Introduction

The formation of the child’s basic neurological and psychological capacities is influenced by neurodevelopmental, biological, and psychosocial factors [1]. The first thousand days of a child’s life play an essential role in a child’s overall development and later mental health [2]. During prenatal, but especially perinatal and infant development brain adapts in response to a wide range of early experiences, which underlie the creation of developmental pathways, i.e., the development of language, cognitive skills, and socio-emotional competencies [3]. These periods are of significant vulnerability and may be influenced by internal and external risk factors that affect fetal and infant development [4]. The fetal programming hypothesis [5,6,7] explains development modeling and points to the impact of certain events occurring during critical points of pregnancy on permanent effects on the fetus and the infant long after birth. The Developmental Origins of Health and Disease (DOHaD) paradigm and the Developmental Origins of Behavior, Health and Disease paradigm (DOBHaD) point to the interrelation between genes and the environments during the prenatal and early postnatal period [8]. These hypotheses emphasize the interdependence of developmental genetic or environmental influences and suggest that human health and development originate in early life [9]. These paradigms also explain how exposure to stress during specific development time can lead to functional changes in tissues, establishing a predisposition for the appearance of the disease in later life [10]. Namely, the DOHaD hypothesis explains (some) adult diseases as a result of in utero programming in conditions of maternal distress (malnutrition, environmental deprivation). Research shows that fetuses whose mothers were malnourished in the second trimester of pregnancy in adulthood show higher tendencies to renal [11] and pulmonary disease [12]. Infants exposed to mothers’ caloric restriction had a higher incidence of mood disorders [13], cardiovascular disease [14,15], and type II diabetes [11] in adulthood. Some studies pointed out that type 2 diabetes mellitus [16], cancer [17], hypertension [18,19,20], and neurodegenerative disorders [21] are associated with modified DNA methylation mechanisms. Few studies show that maternal protein deprivation results in an increase in epinephrine and norepinephrine that can make lasting changes in infants’ circulation, joined with blood glucose dysregulation, hypertension, obesity, small fetal growth, and altered DNA methylation [19,20,22,23,24]. The studies mentioned above pointed to the significant role of epigenetic mechanisms in the DOHaD paradigm.
The current integrative approach is based on the complex interplay between specific models of developmental stages and possible risks, among which maternal mental illness is considered the developmental risk during early child development [1]. Maternal stress during pregnancy needs to be considered as an important risk factor that can affect fetal and child development and behavior, which has been in research focus for many years [25,26,27,28,29,30]. It can be defined as an experience of general stress, anxiety, depressive symptoms, and adverse life situations [30,31]. A significant number of women experience psychological distress during pregnancy and postpartum. More precisely, the prevalence of maternal anxiety ranges from 6.8% to 59.5% [32], while 10–20% of pregnant women experience psychosocial stress and depressive disorders [33,34]. Accordingly, it could be pointed out that stress, anxiety, and depression are the most common mental health problems during pregnancy [35].
This issue is fundamental during the COVID-19 pandemic, which significantly affects maternal mental health [36]. Recent studies looking at this phenomenon during the COVID-19 pandemic have shown elevated anxiety, depression, and stress levels in pregnant and postpartum women and mothers in the postpartum period [37,38,39,40,41]. Considering the adverse effects of maternal distress on child development, the current increase in mental health problems during the COVID-19 pandemic requires monitoring and support for pregnant and postpartum women, as well as support and stimulation of child development.
Generally, the current review aims to direct attention to new findings on the impact of maternal stress, anxiety, and depression on a child’s development, to promote maternal and child well-being, which may be especially significant due to numerous adverse effects of the COVID-19 pandemic. It is organized and presented to explore and describe the effects of maternal distress in pregnancy and the postpartum period on adverse child developmental outcomes. Hence, it briefly summarizes the results of:
  • The latest research on the neurobiology of maternal anxiety, stress, and depression and the transmission mechanisms at the molecular level to the fetus and child;
  • The longitudinal studies in which early child development is monitored to the presence of maternal distress during pregnancy and the postpartum period.

2. Factors and Biological Mechanisms Underlying the Transmission of Maternal Distress to the (Unborn) Child

Fetal development could be considered a sensitive period wherein potential changes in fetal neurobiology may be caused by signals originating from maternal stress experiences and may have a long-lasting effect on the child [42] and developmental programming [43]. Authors Yehuda and Lehrner reviewed the research evidence about parental distress and its possible impact on offspring before birth [44]. The effect of maternal distress on the fetus depends on certain factors which may have a moderating role in the transmission of maternal distress to the (unborn) child. The exposition time [45], period of gestation/pregnancy [46], fetal sex [47], and duration/frequency of maternal distress [48] are factors that may moderate the transmission of maternal stress on the fetus. Some studies pointed out that maternal stress early in gestation may lead to changes in cognitive, behavior, and psychomotor development [49], while other studies pointed to the third trimester of the pregnancy as a specifically vulnerable period during which maternal distress has a more substantial effect on the offspring [47,50,51]. Additionally, the influence of prenatal exposure to maternal distress may be moderated by offspring sex [47,50]. Animal studies demonstrated increased male Hypothalamic–pituitary–adrenal (HPA) stress reactivity, but not female, caused by exposure to chronic stress in utero [52]. On the other hand, human studies demonstrated that female offspring exposed to prenatal maternal stress had higher HPA axis reactivity, with differences in placental expression of 11β-HSD2 (11β-hydroxysteroid dehydrogenase type 2) enzymes, while prenatal stress was associated with alternations in diurnal cortisol secretion in males that were not apparent in females [53]. Recent studies tried to define how prenatal factors could affect gene-specific epigenetic changes in offspring in a sex-specific manner, such as in IGF2/H19 (insulin-like growth factor 2 gene/H19 gene) [54], HSD11B2 (Hydroxysteroid 11-Beta Dehydrogenase 2 gene) [55,56], and exon 1F of NR3C1 (nuclear receptor subfamily 3 group C member 1 gene) [57,58]. Cao-Lei et al. [47] found a significant interaction effect between maternal anxiety in the third trimester and offspring sex on the methylation level of the CpGs of IGF2/H19 ICR and LINE1 motif2 (the long interspersed nucleotide elements 1), but not of the CpGs of NR3C1. This study found a negative association between maternal anxiety and methylation levels in boys and a positive association in girls for IGF2/H19 ICR. Furthermore, maternal anxiety in the second trimester also interacts with sex on the methylation level of LINE 1 motif 2. A previous study revealed a trend-level association between maternal depression and increased NR3C1 methylation for female infants [50]. Taken together, the sex of the child may be essential for epigenetic processes in early childhood since several effects of the sex of the child on changes in DNA methylation patterns were found as a response to maternal anxiety during pregnancy [47].
Although most studies point to the association between maternal distress and offspring development, further clarification on the different contributions of maternal exposure is needed, including the nature of the exposure, the timing of exposure in pregnancy, the sex of the fetus, the nature of maternal symptoms, nutrition, exposure to toxins, delivery factors, medication effects, socio-demographic variables, and other potential mediators [44].

2.1. Mechanisms Involved in Stress Responses

Stress can significantly affect various physiological systems, including the neuroendocrine system, autonomic nervous system (ANS), and immune system [59]. There most often described complex systems that activate neuroendocrine processes as a response to stressors exposure are the hypothalamic-pituitary-adrenal (HPA) axis, the sympathetic-adrenal-medullary (SAM) axis, and the hypothalamic-pituitary-thyroid (HPT) axis.
The HPA axis and the SMA axis are complex systems of neuroendocrine pathways that respond to specific negative feedback loops involving the hypothalamus, anterior pituitary gland, and adrenal gland [60]. The HPA axis presents the major component of the homeostatic response that enables physiological adaptation to the stressor [61]. The activation of both systems is initiated with the release of corticotropin-releasing hormone (CRH) from the hypothalamus, which stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland resulting in the release of glucocorticoid (cortisol) from the adrenal cortex. Cortisol switches off the stress response via a negative feedback mechanism, suppressing the release of ACTH at the pituitary level and CRH at the level of the hypothalamus [62]. The blood concentration of CRH, ACTH, and cortisol increases gradually during the pregnancy, with a rapid increase a few weeks before the parturition [29]. Cortisol level reaches peak concentration in the third trimester of pregnancy [63]. Apart from the importance of the HPA axis during pregnancy, the fetal HPA axis contributes to the constitution of fetal autonomy, having a fundamental role in fetal readiness for birth and survival after birth, while in several species, it determines the timing of birth [64].
At the level of the SAM system, ACTH stimulates the adrenal medulla to release catecholamines (epinephrine and norepinephrine), which are linked to several physiological changes providing an immediate energy source [65]. HPT axes are also involved in stress responses, whereas its final effectors, the Thyroid Hormones (THs), mediate several fundamental processes involved in the neurodevelopment of the offspring [66].
In pregnancy, HPT dysfunction can influence the HPA axis with a direct impact on ACTH and glucocorticoids (GCs) production. While low-circulated THs may decrease cortisol and impair 11β-HSD2 activity, increased THs induce hypersensitivity of cortisol to ACTH [67]. The concentration of GCs and THs must be within the normal range in fetal circulation as they synergistically affect fetal brain maturation and neurodevelopment [66].
Generally, the stress system mainly includes the HPA axis and the ANS [30]. Concerning the sympathetic nervous system (SNS), the primary mediators of the stress system are arginine-vasopressin (AVP), alpha-melanocyte-stimulating hormone, beta-endorphin, and the catecholamines, norepinephrine (NE), and epinephrine (reviewed in Anifantaki et al., 2021) [66].
Several underlying mechanisms of maternal distress transmission to the (unborn) child may operate simultaneously and may amplify each other effects [29]. In the following chapters, the possible mechanisms underlying maternal psychological distress during pregnancy and in the postpartum period will be described.

2.2. Biological Mechanisms and Factors Mediating Maternal Distress in the Prenatal Period

Negative psychological experiences during the pregnancy can trigger the expecting mother and affect her biological mechanisms, including over-activation of the HPA axis in response to stress. This leads to the activation of the mechanisms that cause biological changes in the fetal HPA axis, placental function, fetal brain, and the level of some other functions or processes that may underlie fetal programming.

2.2.1. HPA Axis Dysfunction

Both animal and human studies suggest that the HPA axis plays an essential role in mediating the effects of maternal stress on the fetal brain, consequently affecting the brain and behavior of the offspring [68]. In human pregnancy, the maternal HPA axis becomes less responsive to stress as pregnancy progresses due to the human placental production of CRH, which causes an increase in maternal cortisol [69]. Within the HPA axis, CRH plays a central role in the physiologic response to stress [29]. CRH is responsible for preparing the environment for childbirth during pregnancy [70] and is produced and secreted from the paraventricular nucleus of the hypothalamus. Even though it is crucial for fetal growth [71], under particularly stressful conditions, maternal cortisol concentrations can reach abnormally high levels and consequently reach the fetus in high concentrations, which may potentially alter fetal development and growth [72]. Namely, during exposure to stress, altered activation of the HPA axis results in the elevated release of maternal glucocorticoids (primarily cortisol) that enter into fetal circulation above the normal range, thus influencing a range of biological processes and hormonal changes that the placental mechanism includes. Such processes impact the fetal HPA axis functioning, which affects the developing fetus [73], and leads to abnormalities in cell structure formations, neurotransmission, a function of the fetal central nervous system [74], and may have a long-lasting influence on child development [75]. Finally, early life exposure to excess fetal glucocorticoid (GC) hormones caused by maternal distress can alter normal neuropeptide synthesis and lead to a disruption in the development of the fetal HPA axis, leading to abnormalities in neuroendocrine, behavioral, autonomic, and metabolic functions in adulthood [61].

2.2.2. Placental Mechanism

The placenta is an effective physiological barrier between the maternal and fetal hormonal environments in humans, and it controls fetal exposure to placental and maternal hormones (glucocorticoids, including cortisol) and environmental factors [71]. In pregnancy, from about 8–10 weeks gestation, CRH is also produced by the placenta and has the same biological activity as hypothalamic CRH [29]. Placental CRH (pCRH) is determined to have a major role in mediating the effect of maternal stress on the (unborn) child [76], with secretion to both maternal and fetal compartments. Overproduction of fetal cortisol may arise from maternal cortisol in a fetal compartment and/or from pCHR secretion [29]. Furthermore, maternal stress or anxiety can induce increased transplacental transfer of maternal cortisol to the fetal compartment without an increase in maternal levels [69].
The placenta contains protective enzymes such as monoamine oxidase A, peptides, and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). The 11β-HSD2 is an enzyme that converts cortisol to inactive products such as cortisone and may act as a barrier in transferring elevated levels of GCs from maternal to fetal circulation [77]. Namely, one of the primary roles of the placenta is controlling fetal exposure to maternal cortisol via enzyme 11β-HSD2 [66]. Although there are two forms of 11β-HSD (type 1, 11β-HSD1, and type 2, 11β-HSD2), having significant roles in the bioactivity of glucocorticoids, the predominant form expressed in human placenta is 11β-HSD2 maintaining a concentration gradient between the cortisol levels in the mother’s and the child’s compartments [78]. During pregnancy, 11β-HSD2 expression in the placenta regulates the level of active GCs through the oxidation of maternal corticosteroids into inactive 11-keto derivatives, reducing fetal exposure to active GCs [61]. More precisely, 11β-HSD2, as NAD+− dependent, unidirectionally catalyzes active corticosterone and cortisol conversion to inert 11− dehydrocorticosterone in rodents and cortisone in humans [78]. Thus, as pregnancy progresses, placental 11β-HSD2 constitutes a specific barrier described as the placental glucocorticoid barrier and restrains the transfer of maternal cortisol (whose concentrations in a pregnant woman are several times higher than those observed in the developing fetus) to the fetus, also initiating the development of the fetal HPA axis [78,79]. When a mother is stressed in a way that increases her cortisol level, inactivity of the placental enzyme 11β-HSD2 may leave the fetus vulnerable and less protected from the mother’s circulating hormones, consequently reflecting the hormonal milieu of the fetus [7,71]. Studies in humans demonstrated that maternal distress downregulates the expression and activity of 11β-HSD2, resulting in an alternation in the filtering capacity of the placenta [80] and abnormally elevated levels of CGs in a fetal environment [69]. Recent studies suggest that NR3C1 (nuclear receptor subfamily 3 group C member 1), which is highly expressed in the placenta due to maternal distress, may be an upstream regulator of placental 11β-HSD2 gene expression, increasing the placental sensitivity to GCs [81].
Maternal distress transmission on the level of placental and breastfeeding mechanisms is shown in Figure 1.
Distress can have an impact on the (unborn) child on two levels:
  • Prenatally, the fetus could be affected while still in the uterus via the placenta and dysregulated maternal HPA axis;
  • Postnatally, the newborn infant could be affected via breastfeeding and changed milk composition (disrupted concentrations of hormones, immune cells, and other components).

2.2.3. Catecholamine, Uteroplacental, and Fetal Hemodynamics

Maternal distress may also cause a reduction in the fetoplacental blood supply which is a critical determinant of placental function and fetal growth and another essential part of a placental mechanism [30]. A recent animal study demonstrated that chronic prenatal psychosocial stress during the first and second trimesters could increase fetal catecholamine concentration [45]. The release of stress hormones, such as corticosteroids and catecholamines, strongly affects the tone of peripheral blood vessels [29]. These hormones, which are products of the SAM axis, stimulate α and β neuroreceptors in the placenta, resulting in vasoconstriction of the uteroplacental vessels. Norepinephrine stimulates α-adrenoceptors leading to increased blood pressure, constriction of blood vessels, and decreased uterine blood supply. On the other hand, norepinephrine increases the production of pCRH and causes a series of endocrine interactions that may affect pregnancy and fetal development [60].

2.2.4. Immune System and Inflammation as Maternal Mediators of Stress

There is evidence of mediating role of the immune system and inflammation in the transmission of maternal stress [68,69]. Pro-inflammatory cytokines and their altered patterns during pregnancy have been associated with maternal psychosocial stress, depression, or anxiety [82,83]. Elevated maternal stress in early and late pregnancy has been associated with elevated production of the pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor (TNF-α), suggesting that stress affects immune system cells [69,84], and may be associated with increased risk of fetal outcomes [85]. Studies examining cytokines’ role in mother–fetus interaction demonstrated that pro-inflammatory cytokines such as TNFα, IL-1β, and IL-6 do not cross the placenta during normal pregnancy [86,87]. On the other hand, increased TNFα, IL-1β, and IL-6 in the amniotic fluid expresses an inflammatory process, which may lead to an increased risk of premature delivery, cerebral palsy, and bronchopulmonary dysplasia in offspring [86].
Evidence on this topic is limited and inconsistent, derived mainly from animal models [88].

2.2.5. Serotonin and Tryptophan

Data about the neurotransmitter serotonin (or 5-hydroxytryptamine, 5-HT) and tryptophan in maternal–fetal stress transmission is limited, especially in humans. Serotonin is synthesized from tryptophan and has a crucial role in fetal brain development [89]. Studies in animals pointed to the potential role of serotonin and tryptophan in fetal programming [90]. Molecular alterations observed in animal models exposed to prenatal maternal stress include: turnover of serotonin (5HIAA/5-HT ratio, (5-hydroxyindoleacetic acid/serotonin)) in the hippocampus, increased TPH (tryptophan hydroxylase) expression, and serotonin level in the dorsal raphe nuclei, increase the 5-HT1A receptor (serotonin 1A receptor) in the hippocampus, and the decrease in SERT (serotonin transporter or 5HTT) levels in the offspring who may have a manifestation of depression in later life (reviewed in St-Pierre et al., 2016) [89]. Maternal depression during pregnancy may be associated with the downregulation of enzyme monoamine oxidase A (MAO A), thus affecting the transplacental serotonin passage from the mother to the fetus [91]. Thus, the potential programming role of serotonin may be defined by the modification of the serotonin systems (maternal, placental, and fetal serotonin systems) caused by maternal distress during a sensitive period of early development, which may affect fetal development and increase the risks of anxiety, depression, and autism later in life [30,89,92].

2.2.6. Oxidative Stress: Interaction between Maternal and Fetal Oxidative Systems

Fetal programming may be influenced by maternal oxidative stress and reactive oxygen species (ROS), which in excessive concentrations, can induce severe cell damage by oxidation of lipids, proteins, and DNA (deoxyribonucleic acid) [88]. The modification of the fetal epigenome is caused by the intracellular ROS, which decreases the activity of the nuclear DNA epigenetic control mechanisms inducing global DNA-hypo-methylation [93] and interfering with the control of histone methylation [94].

2.2.7. Neuroactive Steroids

The primary neuroactive steroids proposed to play a role in fetal programming are allopregnanolone and 5α,3α-tetrahydrodeoxycorticosterone (THDOC). Both are potent modulators of GABAergic inhibitory and neuronal functions and modulate HPA axis function. It was demonstrated that stress could reduce circulating levels of allopregnanolone at birth, resulting in reduced production in the offspring’s brain. The reductions in neuroactive steroids may be linked with cognitive impairments and anxiety-evoking effects [88].

2.2.8. Maternal Microbiota as a Potential Stress-Transfer Mechanism

Maternal microbiota and its vertical transmission to the fetus or newborn is rather hypothetical than demonstrated stress-transfer mechanisms [88]. This mechanism refers to the programming of the fetal gut–brain axis caused by impaired maternal microbiota, which is linked to maternal stress. The bi-directional communication system between the gastrointestinal tract and the brain (so-called gut–brain axis) includes neuronal, immune, and endocrine pathways (involving cytokines, neurotransmitters, and other neuromodulators) and potentially is associated with neurodevelopmental and psychiatric diseases [30,45]. The stress-induced modulation of the ‘gut-brain’ axis changes the enteric synthesis of neuroinflammatory cytokines, neuromodulators, and neurotransmitters involved in the newborns’ neurodevelopment, which may lead to a greater susceptibility to neuropsychiatric disease in later life [95].

2.2.9. Autonomic Nervous System

Apart from the HPA axis, the autonomic nervous system is the second major stress response system. The ANS is divided into two main branches: the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS), which regulate heart rate (HR). Heart rate and heart rate variability (HRV) have been associated with both higher and reduced baseline fetal HR in pregnancies burdened with maternal prenatal stress, anxiety, and depression (reviewed in Vehmeijer et al., 2019) [30]. On the other hand, the involvement of ANS activity in the maternal–fetal stress transfer mechanism is demonstrated in increased catecholamines which induce vasoconstriction of the uteroplacental vessels and consequently lead to the reduction of uteroplacental blood flow, which is previously described. There is no conclusive evidence of a clear association between maternal and fetal autonomic functioning in the presence of maternal stress during pregnancy and their potential links with fetal/child health outcomes [30,51].

2.2.10. Gene–Environment Interactions, Epigenetics, and Prenatal Stressors

The development of the fetus’s brain regions and cognitive-emotional functions is assumed to depend on gene–environment interactions [69]. Some children are affected by the various forms of prenatal stress to develop later child psychopathology, while some are not. The “genetic makeup” of the child related to environmental factors is, at least partially, the reason for this distribution [69]. This is under the differential susceptibility framework of gene–environment examinations, which suggests that an individual’s biological context moderates sensitivity to both positive and negative environmental influences; and views traditionally labeled “vulnerable” individuals as “plastic/malleable” individuals [1].
Gene–environment interactions may cause epigenetic changes in gene expression patterns and thus affect or create a specific phenotype of human psychophysiological abilities or disease. Namely, the genome, epigenome, and environment act simultaneously and thus create certain phenotypic traits in humans [96]. The suggested ‘Fetal programming’ mechanism, according to the DOHaD hypothesis, points to a relationship between adverse environmental effects and genetic and epigenetic modifications during critical prenatal and later human health or disease [47]. The term “epigenetic” refers to alterations in gene function in the absence of changes in the DNA sequence. In contrast, the term “epigenom“ refers to chemical modifications to DNA, chromatin, and histone structure, nucleosome positioning, and functions of non-coding ribonucleic acid (RNA) [97]. Furthermore, the three primary molecular epigenetic mechanisms comprise DNA methylation, histone modifications, and non-coding RNAs. DNA methylation refers to the covalent modification of cytosine with a methyl group, histone modification includes acetylation, methylation, phosphorylation, and ubiquitination, while microRNA refers to small non-coding RNAs with post-transcriptionally regulated gene expression [98].

DNA Methylation

DNA methylation (DNAm) is a biological process involving a post-replication enzymatic modification of DNA, which refers to binding the methyl group to carbon in position five of the cytosine ring. It can change the activity of a DNA segment without changing the sequence. Under normal conditions, DNA methylation is essential for normal development. It is associated with several critical processes involved in the transcriptional silencing of genes, regulation of expression of imprinted genes, some tumor suppressor genes in cancer, and silencing of genes located on the inactive X chromosome [99]. On the other hand, DNA methylation may be modified by prenatal maternal and fetal stressors, thus affecting downstream gene expression, neuroendocrine functioning, and behavioral development [98].
Several genes are involved in response to stress via the HPA axis, autonomic nervous system hyperactivity, and cortical and subcortical processes of neuroplasticity and neurodegeneration based on changes in the scope of their expression. These genes have been targeted based on the hypothesis that methylation alterations mediate stress’s biological effects. These genes include: the corticotrophin-releasing hormone gene (CRH gene), arginine vasopressin gene (AVP gene), glucocorticoid receptor gene nuclear receptor subfamily 3 group C member 1 (NR3C1), FK506 binding protein 5 gene (FKBP5), Solute carrier family 6 member 4 gene (SLC6A4) which is a serotonin transporter, also known as the 5-HTT gene, and brain-derived neurotrophic factors [96,100].
Furthermore, infant neural functions may be directed by the influence of the prenatal emotional disturbances of the mother via DNA methylation of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) and glucocorticoid receptor nuclear receptor subfamily 3 group C member 1 (NR3C1), which are two placental genes that have been implicated in perturbations of the HPA axis [101].
The NR3C1 gene and the region of exon 1F have been extensively studied regarding disturbed emotional states (depression and anxiety) during pregnancy [47,101,102,103] and associated with DNA methylation changes (higher methylation levels) of placental NR3C1 exon 1F. Apart from the NR3C1, in the study of Martinez et al. [70], a significant increment in the gene expression of the hydroxysteroid dehydrogenase (HSD11B2) encoded by the enzyme 11ß-HSD2 was demonstrated, which consequently may negatively affect the neurodevelopmental outcomes of the newborn. The placental 11β-HSD2 enzyme converts active cortisol into inactive cortisone, thus regulating the degree to which cortisol can pass through the placenta and protecting the fetus from excessive glucocorticoid exposure [80]. Increased placental DNA methylation led to decreased expression of 11β-HSD2 in infants with the lowest birth weight [101,104]. Modified gene expressions can consequently be associated with adverse effects on poor newborn neurodevelopmental outcomes, such as lower birth weight and reduced newborn movement quality [70,105].
Increased placental FK506 Binding Protein 51 (FKBP51) methylation is associated with reduced fetal coupling and potentially predicted neurobehavioral development of the newborn due to higher perceived stress in the mother [104].
Among the other relevant genes enrolled in prenatal stress is Solute carrier family 6 member 4 (SLC6A4). It is a widely studied gene that encodes serotonin transporter [98]. Maternal depressive symptoms during pregnancy can be associated with decreased gene methylation status in children [106].
There are limited findings about oxytocin receptor gene (OXTR) methylation caused by maternal distress. Both a decrease and increase in infant OXTR methylation were associated with maternal distress (reviewed in Sosnowski et al., 2018) [107].
Furthermore, the brain-derived neurotrophic factor (BDNF) plays a role in neural cell growth, maturation, and maintenance. The opinions are opposite, but some studies detected a significant association between prenatal depressive symptoms and decreased BDNF promoter IV DNA methylation in buccal DNA in infants [98].
DNA methylation of specific imprinted genes may also be associated with maternal mental health during pregnancy. The insulin-like growth factor 2 gene (IGF2 gene) plays an essential role in fetal growth and development, while the H19 gene is located in an imprinted control region (ICR) of chromosome 11 near the IGF2 gene and is expressed from the maternally-inherited chromosome. There are inconsistent findings indicating both increased and decreased DNA methylation of IGF2/H19 ICR in the placental and cord blood of children exposed to higher levels of maternal anxiety [54,108], additionally influenced by the sex of the child [47]. There are other imprinted genes such as MEG3 (Maternally Expressed gene 3), PLAGL1 (PLAG1-Like Zinc Finger 1), PEG3 (Paternally Expressed 3) associated with DNA methylation in offspring who experienced prenatal maternal distress (reviewed in Cao-Lei et al., 2020; reviewed in Ryan et al., 2017) [73,98].
The long interspersed nucleotide elements 1 (LINE1) as an indicator of global DNA methylation status was also examined concerning DNA methylation in children whose mothers experienced high levels of distress during pregnancy. Cao-Lei et al. (2021) [47] found higher methylation in boys and lower in girls for LINE1 motif2 exposed to prenatal maternal distress.

Histone Modification

Histone modification is an epigenetic mechanism for regulating gene expression, which may be induced by the response to DNA methylation or by intracellular signaling pathways independent of DNA methylation [97]. Several histone modifications include acetylation, phosphorylation, methylation, deimination, ADP-ribosylation, ubiquitylation, sumoylation, and proline isomerization [109]. This mechanism affects the chromatin structure, which plays an essential role in DNA packaging, gene transcription, and cross-talk between DNA methylation and chromatin configuration [97], and may lead to the activation or suppression of gene expression. In animal studies, histone modifications have been reported to be crucial targets for interacting with the early stress response system and manifesting later depressive and long-term adverse effects such as preclinical and clinical development of depression, anxiety, depression-like behaviors, and development of psychiatric diseases, such as major depressive disorder in adulthood [110,111].

Changes in Non-Coding RNAs

Non-coding RNAs (ncRNAs) are untranslated RNA molecules that regulate gene expressions. These are small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), circular RNAs (cRNAs), and piwi-interacting RNAs (piRNAs) [112]. In a recent review, it was demonstrated that ncRNAs might impact the epigenome in the context of different environmental risk factors, including mental stress, and contribute to the pathophysiology state [113].
Finally, despite large evidence to suggest that epigenome corresponds with altered gene expression in children exposed to maternal distress during pregnancy, there is a lack of reproducible findings and potential limitations, which imposed the need for further research in this research field.

2.2.11. Neurodevelopmental Mechanisms

The transmission of maternal stress hormones, especially glucocorticoids, across the placenta to the fetus may play a critical role in fetal neurodevelopment [1]. Evidence indicated that overexposure to maternal glucocorticoids caused by downregulation of 11β-HSD2 mRNA expression and activity is a significant predictor of spontaneous preterm birth and low birth weight [114]. Higher levels of maternal cortisol tend to cause alterations in the neural activity of the babies, and it refers to increased low-frequency brain activity (i.e., higher relative theta power) and decreased high-frequency brain activity (i.e., less relative alpha and higher-gamma power and marginally less beta power). This study indicates that a mother’s chronic psychological stress negatively affects the newborn’s developmental patterns of brain activity [115]. Maternal anxiety during pregnancy may be related to specific changes in brain morphology depending on exposition time. It was demonstrated that maternal anxiety at 19 weeks gestation has been associated with grey matter volume reductions in the prefrontal cortex, the premotor cortex, the medial temporal lobe, the lateral temporal cortex, the postcentral gyrus, and the cerebellum extending to the middle occipital gyrus and the fusiform gyrus [116]. A recent study examining the association of prenatal maternal psychological distress with fetal brain growth, metabolism, and cortical maturation found impaired fetal brain biochemistry and hippocampal growth, and accelerated cortical folding [117].
On the other hand, maternal anxiety during pregnancy has been linked to problems in infant temperament, behavior, and cognitive development; emotional and behavioral problems in children and adolescents; and structural brain [1]. In the review article of Van den Bergh et al. [7], the studies that have observed fetal behavior of highly anxious or stressed mothers were presented; the results indicated more bodily activity and spontaneous motor activity in the observed fetuses. Furthermore, these infants exhibited more frequent behaviors such as crying, irritability, irregularity of biological functions, gripes, and difficult temperament, postnatally. Male children from these studies exhibited increased activity, attention deficit, and aggressiveness at nine years.

2.3. Biological Mechanisms Underlying the Maternal Distress Transmission to the Child in the Postpartum Period

Biological mechanisms underlying maternal distress transmission to the child in the postpartum period are described through breastfeeding, mother-child bonding, and caregiving mechanism.
Breastfeeding appears to be very beneficial for the mother and her child. However, postpartum depression might have adverse effects on maternal self-esteem and cognition. Inadequate bonding between women with depressive symptoms and their newborns increases the risk of breastfeeding difficulties [118].
Breast milk is the best food for infants, containing all the nutrients they need for normal development and health. Breast milk composition presents a mediatory mechanism connecting perinatal psychopathology with a child’s brain development. Maternal perinatal psychopathologies, such as depression, anxiety, and stress, determine strong biological alterations in the affected women, which can change breast milk’s regular composition (Figure 1). Given that breast milk has an essential role, an alteration in its composition can severely affect child neurodevelopment, impairing fundamental functions related to cognition, behavior, and attention [119].

2.3.1. Effects of Maternal Distress on Milk Composition

In the study by Semir Demirgoren et al. [120], it has been shown that mothers with postnatal depression and state anxiety had higher than expected breast milk Na concentrations and a high NA/K ratio (sodium levels and sodium/potassium ratio in breast milk). The anxiety symptoms that appear postnatally in a specific moment (state anxiety) can affect more significantly the composition of breast milk compared to the woman’s personality and proneness to anxiety (trait anxiety) [119]. This study confirmed that increased breast milk Na and Na/K ratio is associated with mothers’ depressive and anxious symptoms in the postpartum period, with possibly severe consequences in infants [120].
However, Kim et al. [121] have recently found that no endocrine-disrupting chemicals in milk were significantly associated with developing postpartum depression. The authors have noted that concentrations of mono-2-Ethylhexyl phthalate and ethylparaben in breast milk were positively associated with the risk of postpartum depression in the group of Korean mothers.
Nevertheless, the information about toxic metal concentrations in breast milk is limited. The association between metal breastmilk concentration and maternal distress in the postpartum period should be further investigated.
Shariat et al. [122] have found a significant positive association between milk transforming growth beta factor-2 (TGFβ2) concentration and both postpartum depression and anxiety.
Secretory IgA (sIgA), a vital component in the first-line defense of the immature immune system and microbiota development in early life, was significantly decreased in infants born to mothers with pre and postnatal depressive symptoms. This study suggested that lower sIgA concentrations in these infants predispose them to a higher risk for allergic disease [123].
Following these results, Kawano and Emori [124] found a negative association between maternal postpartum psychological state and breast milk sIgA levels, concluding that maternal psychological state may affect the immune components of breast milk.
Furthermoref, another study showed that postpartum stress could be associated with reduced sIgA concentration, suggesting that women may have reduced breast milk immunological benefits, thus offering less immunological protection to their infants [125].
However, the authors Aparicio et al., 2020 found that maternal psychosocial distress was positively related to higher milk cortisol concentrations at week two post-delivery but generally concluded that there is no evidence for an association between natural variations in maternal distress and immune factor concentrations in milk [126].
Based on the evidence from their recent study, the authors suggested that the mother’s psychological well-being may be related to the immunological components of her milk, according to the fact that increased anxiety negatively affects milk’s immune properties. Concerning positive mental health factors, maternal social support was found to be correlated with milk IgG [127]. Pregnancy and lactation may exacerbate low Docosahexaenoic acid (DHA) status because maternal DHA stores are mobilized to support the rapid development of the fetal and infant brain [128].
Rather than transient depressive symptoms during the pregnancy, low breast milk DHA may reflect chronic depression more closely, given that breast milk DHA levels largely reflect fatty acid stores laid down over many years. The association between depressive symptoms early in pregnancy and reduced DHA breast milk levels appeared significant in the study of Keim et al. [129].
Ziomkiewicz et al. [130] found a significant and negative effect of maternal stress during the postpartum period on the composition of breast milk. Perinatal psychosocial stress negatively affected energy density, fat, and medium-chain and long-chain saturated fatty acids in milk. Higher cortisol level secreted was positively associated with the content of long-chain mono- and polyunsaturated fatty acids and lower lactose content in milk.
The predictor of severe depressive symptoms in postpartum women was higher thyroxine levels, while the predictor of depression appearing 6–10 weeks postpartum was higher progesterone and lower prolactin levels. Women who had previous episodes of depression had decreased prolactin and increased thyroid-stimulating hormone levels than those who had experienced depressive symptoms before [131].
In a prospective cohort study, Stuebe et al. [132] found that higher depression and anxiety symptoms were correlated with lower levels of oxytocin in response to breastfeeding at eight weeks postpartum. These results suggest that maternal psychological symptoms are associated with neuroendocrine changes in lactation.
According to a few studies, there are indices that maternal distress can be associated with changed maternal milk composition; however, this field is not yet explored enough. The mechanism of transferring through breastfeeding is possible, and molecular pathways are the direction for future examinations.
A positive relation was found between maternal psychosocial distress and breast milk cortisol levels in the early postnatal period [126]. A recent study revealed that preterm infants are born deficient in transplacental hormones such as TSH, thyroxine, and albumin because their intrauterine development is interrupted early [133]. Furthermore, another study revealed that stress reactivity was associated with milk components, such as milk energy density, fat, medium-chain, and long-chain saturated fatty acids [127,130,134]. A recent study by Kortesniemi (2021) found that the human milk metabolome is associated with maternal psychological distress and milk cortisol concentration, pointing to stress-induced changes in the microbiome–gut–brain axis and energy metabolism [135].

2.3.2. Mother-Child Bonding and Caregiving Mechanism

Maternal distress has multiple effects on a child’s development, including the neurodevelopmental impact of stress-related hormones and the psychosocial impact of parenting behavior. This focus is central to the development of integrative models for the development of psychopathology [1].
Attachment theory proposes an integrative framework of human development, where development occurs in the context of early relationships, which provide security and comfort [136].
Cooke et al. [137] investigated maternal attachment insecurity and depression symptoms and acted as an intermediary mechanism of mothers’ adverse early experiences contributing indirectly to the intergenerational transmission of risk for children’s behavioral and psychological symptoms. Both maternal attachment avoidance and attachment anxiety in adulthood contributed to these pathways. In contrast, maternal anxiety symptomatology was not found to significantly mediate these pathways [137].
The immature brain of the infant reacts differently to various ways of stimulation or insufficient stimulation, and these effects are related to elevated catecholamines, delays in myelination, and synaptic pruning [1].
Indeed, a growing body of evidence suggests the epigenome is also responsive to social and environmental exposures due to its role in cellular programming, during intra-uterine development and after birth. Exposure to stress early in life may affect the epigenome, but these effects may be silent depending on whether the system is triggered or not throughout life by any factors [138].
The authors studied the impact of maternal care on the epigenetic programming of the NR3C1 gene promoter in the rat hippocampus and found that DNA methylation patterns of the NR3C1 gene can be altered after birth in response to the social environment [138,139].

3. Maternal Distress as a Risk Factor for Adverse Fetal and Child Developmental Outcomes

From all the above, it follows that maternal distress is a risk factor that can significantly affect fetal psychophysiological development and is often positively correlated with pre and perinatal risk factors. Recent research shows that elevated levels of maternal stress, anxiety, and depression during pregnancy are associated with the risk of preeclampsia, prematurity, low birth weight, and poorer neonatal outcome [140,141,142].
Furthermore, it is essential to point out that maternal distress may often be associated with specific changes in brain morphology and abnormalities in the functioning of the central nervous system [116,143]. These specific changes in brain function and morphology lead to vulnerable early development of the human individual, which is re-percussed on later development as well. Maternal prenatal distress affects the outcome of the pregnancy and results in early programming of fetal brain functions with permanent changes in neuroendocrine regulation and offspring behavior [68,69]. The impact of maternal distress during pregnancy on fetal outcomes and child cardio-metabolic, respiratory, atopic, and neurodevelopment-related health outcomes is also well documented [30]. Generally observed, the underlying risk factors caused by maternal distress are associated with various aspects of further child development, such as cognition, speech-language development, motor development, behavioral and learning difficulties, socio-emotional development, and neurodevelopmental disorders [9,144,145,146].

3.1. Cognition

Cognitive development is a complex mental process based on the ability of the comprehension and process information. The lower mental development of children might be affected by mothers’ prenatal exposure to distress. Several studies found that women exposed to stressful life events such as natural disasters as well as prenatal distress had a significantly increased risk of children with poorer cognitive development at different ages [147,148,149,150]. Trait anxiety in the second trimester and both trait and state anxiety at 32 gestation weeks predicted lower mental developmental scores in children aged 8 and 24 months [147,148]. Elevated maternal cortisol levels in late pregnancy were associated with lower mental development in children aged 3 months [148]. Unlike previous studies, the study of Keim et al. [151] indicates that pregnancy-specific anxiety very poorly correlates with overall mental development at 12 months of age.
Studies dealt with the influence of maternal distress during pregnancy on language development as well as language skills such as reading, spelling, writing, and mathematics skills (numeracy), most often comparing the impact of mothers’ distress on the development of receptive and expressive language in children. Research findings pointed to lower productive language abilities and receptive language in toddlers aged 30 months who were prenatally exposed to maternal distress [149]. On the contrary, a study conducted by Keim et al. [151], in which the association between prenatal and postnatal anxiety, stress, and depressive symptoms on language ability of 12-month-old infants was examined, pointed to better language skills in children whose mothers had higher depression symptoms. The impact of prenatal maternal distress on specific learning abilities (literacy and numeracy) in children aged 10 was examined in a large population follow-up study [152]. This study pointed to the significant difference between genders: girls had lower accomplishments in reading, while no association was found between prenatal distress and spelling, writing, and numeracy, compared to boys whose mothers experienced maternal distress. On the other hand, boys whose mothers had three or more stressful events during pregnancy had higher scores on numeracy and writing test compared to boys from the control group.

3.2. Socio-Emotional Development

Socio-emotional development is a complex process that involves the interaction of maturation factors and the child’s environment. Some studies reported an association between maternal distress during pregnancy and postpartum and poorer socio-emotional development [75,153,154]. Further, a small study of mother-infant dyads [143] used diffusion tensor imaging (DTI) pointed out the association between the internalizing domain of behavior and neonatal insula variation in infants whose mothers had prenatal distress.
Numerous studies have described the impact of maternal distress on various aspects of temperament [150,155,156]. Infants between 16–18 months whose mothers experienced more stressful life events during early pregnancy (first trimester) had low regularity, persistence, and attention span [150]. Likewise, pregnancy-specific anxiety was a positive predictor for 6-months-old infant fearfulness and falling reactivity [155], while infants whose mothers were exposed to higher levels of distress during the first trimester of pregnancy (illness/infection conditions, older mothers, subject distress) were found less responsive [157]. Furthermore, at six months of age, pregnancy-related anxiety can be a predictor of mood disturbance [140].
Trait anxiety in late pregnancy predicts a more difficult temperament in infants, while state anxiety and pregnancy-related anxiety had no significant effect on temperament [158].
Few studies tried to determine whether mothers’ distress during pregnancy predicts the value of mother-infant bonding postpartum. During the COVID–19 pandemic, the study examined mother-infant dyads for 3 months, and the results showed that lower levels of maternal anxiety at delivery are correlated with higher mother-infant bonding. On the other hand, in another study, a positive correlation was found between prenatal pregnancy anxiety, postpartum trait anxiety, postpartum depression, and postpartum bonding, but a significant association was found between pregnancy-related fear, postnatal anxiety, and mother-infant bonding [159]. One particular study examined the multimodal processing of face and voice pairs regarding fearful and happy emotions in 9-month-old infants [160]. The authors hypothesized that non-typical experiences, such as mothers’ distress during fetal development, can alter the development of this ability, and the results of the study showed that general anxiety, but not state anxiety, had significant effects on the processing of emotional information.

3.3. Fine and Gross Motor Development

Motor development involves the development of two aspects of motor skills: fine and gross motor skills. Studies assessing infants’ motor development at 24–30 months [75] and 36 months of age [161] indicated that high prenatal maternal anxiety was associated with poorer gross motor development related to delays in fine and gross motor development and problem-solving domains.
Furthermore, fine and gross motor development was assessed in children at 2, 6, and 16 months [146]; 10 months [162]; and 12 and 24 months [147]. At 2 months, fine and gross motor skills were positively correlated with maternal peritraumatic distress levels. However, at 6 months, fine and gross motor skills were negatively correlated with maternal distress. No significant association was found between fine gross motor functioning and maternal distress at 16 months of age, while gross motor skills were negatively correlated with maternal distress [146]. Further, at 10 months of age negative correlation was found between maternal trait anxiety and fine motor skills, while no significant correlation was found between maternal anxiety and gross motor skills, visuomotor function, and brain stem function [162]. Moreover, at the ages of 12 and 24 months, the motor development of infants who were exposed to maternal distress during pregnancy was observed within the overall development [147]. This study’s results indicated lower scores on the motor scale in infants exposed to higher maternal distress at the ages of 12 and 24 months.
The longitudinal study assessed the effects of objective and subjective prenatal maternal stress of pregnant women exposed to a natural disaster on the motor development of 5½ years old children and showed a correlation between prenatal maternal stress and bilateral coordination and visual-motor integration [163]. Finally, the study investigated the long-term effects of the number and timing of stressors experienced during pregnancy on motor development at 10-, 14- and 17-years old children [164] and indicated that children whose mothers had more than three distressing events during pregnancy had lower motor competence at all tested ages. This result implicated that number of experienced prenatal stresses may have a cumulative effect on offspring motor development.

3.4. Neurodevelopmental Disorders

The most frequent neurodevelopmental disorders, which are characterized by developmental deficits that produce impairments of personal, social, academic, or occupational functioning, are: attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) [165]. Several studies have been investigating maternal prepartum and postpartum distress as risk factors for ASD and ADHD [166,167,168], pointing to the association between prenatal stress and a higher frequency of diagnoses of ASD or ADHD in children after the age of 3. Gender differences (for ADHD diagnosis) [168] and time of exposure to stress during pregnancy were found to be significant for both ASD (first and third trimester) and ADHD (third trimester) [167]. Some studies focusing on the symptoms of ASD and ADHD in children whose mothers experienced prenatal distress showed that both boys and girls, not gender-related, at the age of 6 years and 6 months scored higher on autism-like traits, especially when mothers experienced more than one stressful event during pregnancy [169] while only boys were likely to be at a higher risk for ADHD symptoms [170]. On the other hand, a study focusing on the diversity of autism symptoms in children already diagnosed with ASD who have been exposed to distress during intrauterine development [171] found that the symptoms of autism are more severe only in those children whose mothers experienced more than one stressful event during pregnancy. The symptoms were significantly increased in the domain of behavior (repetitive and restricted behavior), communication, and language (syntax, semantics, coherence, and stereotyped language). The obtained results may indicate that prenatal stress can alter ASD phenotype.
Reviewed studies implicate the association between prenatal maternal distress and specificity/delays in cognitive, socio-emotional, and motor development in infants and children, but neurobiological mechanisms underlying these developmental delays need to be further examined.

4. Conclusions

In addition to the well-known adverse effects of biomedical risks, the mother’s psychological factors can significantly contribute to complications in pregnancy and the unfavorable development of the (unborn) child. Maternal distress must be monitored prenatally and in the postpartum period concerning specific biological transmission mechanisms. This topic gained importance because of the numerous adverse effects of the COVID-19 pandemic, during which a higher frequency of maternal psychological disorders was observed. The need for further interdisciplinary research on the relationship between maternal mental health and fetal/child development was highlighted, especially on the biological mechanisms underlying the transmission of maternal distress to the (unborn) child, to achieve positive developmental outcomes and improve maternal and child well-being.

Author Contributions

Conceptualization, L.J. and M.S.; methodology, L.J.; data collecting and analysis, L.J., A.V. and M.Ć.; writing—original draft preparation, L.J., A.V. and M.Ć.; writing—review and editing, L.J., M.S., V.J. and S.R.; visualization. A.V. and M.Ć.; supervision, M.S. and V.J.; project administration, L.J. All authors have read and agreed to the published version of the manuscript.


This work was partially supported by the Ministry of Education, Science and Technological Development of The Republic of Serbia within the project “Influence of psychophysiological, sociological, and cultural factors on speech and language in the child population”. This project is realized in cooperation with the Faculty of Medical Sciences, University of Kragujevac, Serbia. Furthermore, Ljiljana Jeličić is working group member of COST Action CA18211: DEVoTION: Perinatal Mental Health and Birth-Related Trauma: Maximizing best practice and optimal outcomes.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


DOHaDDevelopmental Origin of Health and Disease
DOBHaD Developmental Origins of Behavior, Health and Disease
COVID-19 Coronavirus Disease 2019 caused by SARS-CoV-2 virus
HPA Hypothalamic–pituitary–adrenal
CRH Corticotropin releasing hormone
ACTH Adrenocorticotropic hormone
11β-HSD211β-hydroxysteroid Dehydrogenase type 2
11β-HSD111β-hydroxysteroid Dehydrogenase type 1
NAD+Nicotinamide adenine dinucleotide
IGF2Insulin-Like Growth Factor 2
H19H19 Imprinted Maternally Expressed Transcript
HSD11B2Hydroxysteroid 11-Beta Dehydrogenase 2 gene
NR3C1Nuclear receptor subfamily 3 group C member 1
LINE 1The long interspersed nucleotide elements 1
DNADeoxyribonucleic acid
RNARibonucleic acid
ANSAutonomic nervous system
SAM axisSympathetic-adrenal-medullary axis
HPT axisHypothalamic-pituitary-thyroid axis
THsThyroid Hormones
SNSSympathetic nervous system
PNSParasympathetic nervous system
TNF-αTumour necrosis factor
5-HT5-hydroxytryptamine or serotonin
5HIAA5-hydroxyindoleacetic acid
TPHTryptophan hydroxylase
5-HT1A Serotonin 1A receptor
SERTSerotonin transporter or 5HTT
MAO AMonoamine oxidase A
ROSReactive oxygen species
HRHeart rate
HRVHeart rate variability
DNAmDNA methylation
FKBP5FK506 binding protein 5 gene
SLC6A4Solute carrier family 6 member 4 gene
5-HTT geneSerotonim transporter gene (or SLC6A4 or SERT)
FKBP51FK506-binding protein 51
OXTROxytocin receptor gene
BDNFBrain-derived neurotrophic factor
ICRImprinted control region
MEG3 geneMaternally expressed gene 3
PLAGL1 genePLAG1-Like Zinc Finger 1 gene
PEG3 genePaternally expressed gene 3
ncRNAsNon-coding RNAs
snRNAsSmall nuclear RNAs
snoRNAsSmall nucleolar RNAs
rRNAsRibosomal RNAs
tRNAsTransfer RNAs
cRNAsCircular RNAs
piRNAsPiwi-interacting RNAs
TGFβ2Transforming growth beta factor-2
sIgASecretory IgA
DHADocosahexaenoic acid
ADHDAttention deficit hyperactivity disorder
ASDAutism spectrum disorder


  1. Newman, L.; Judd, F.; Olsson, C.A.; Castle, D.; Bousman, C.; Sheehan, P.; Pantelis, C.; Craig, J.M.; Komiti, A.; Everall, I. Early origins of mental disorder-risk factors in the perinatal and infant period. BMC Psychiatry 2016, 16, 270. [Google Scholar] [CrossRef] [PubMed][Green Version]
  2. Black, M.M.; Walker, S.P.; Fernald, L.C.; Andersen, C.T.; DiGirolamo, A.M.; Lu, C.; McCoy, D.C.; Fink, G.; Shawar, Y.R.; Shiffman, J. Early childhood development coming of age: Science through the life course. Lancet 2017, 389, 77–90. [Google Scholar] [CrossRef][Green Version]
  3. Britto, P.R.; Lye, S.J.; Proulx, K.; Yousafzai, A.K.; Matthews, S.G.; Vaivada, T.; Perez-Escamilla, R.; Rao, N.; Ip, P.; Fernald, L.C. Nurturing care: Promoting early childhood development. Lancet 2017, 389, 91–102. [Google Scholar] [CrossRef][Green Version]
  4. Van den Bergh, B.R. Developmental programming of early brain and behaviour development and mental health: A conceptual framework. Dev. Med. Child Neurol. 2011, 53, 19–23. [Google Scholar] [CrossRef] [PubMed][Green Version]
  5. Gluckman, P.D.; Hanson, M.A.; Pinal, C. The developmental origins of adult disease. Matern. Child Nutr. 2005, 1, 130–141. [Google Scholar] [CrossRef]
  6. Gluckman, P.D.; Hanson, M.A. Developmental origins of disease paradigm: A mechanistic and evolutionary perspective. Pediatric Res. 2004, 56, 311–317. [Google Scholar] [CrossRef][Green Version]
  7. Van den Bergh, B.R.; Mulder, E.J.; Mennes, M.; Glover, V. Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: Links and possible mechanisms. A review. Neurosci. Biobehav. Rev. 2005, 29, 237–258. [Google Scholar] [CrossRef]
  8. Wadhwa, P.D.; Buss, C.; Entringer, S.; Swanson, J.M. Developmental origins of health and disease: Brief history of the approach and current focus on epigenetic mechanisms. In Seminars in Reproductive Medicine; © Thieme Medical Publishers: New York, NY, USA, 2009; pp. 358–368. [Google Scholar]
  9. Ibanez, G.; Bernard, J.Y.; Rondet, C.; Peyre, H.; Forhan, A.; Kaminski, M.; Saurel-Cubizolles, M.-J.; Group, E.M.-C.C.S. Effects of antenatal maternal depression and anxiety on children’s early cognitive development: A prospective cohort study. PLoS ONE 2015, 10, e0135849. [Google Scholar] [CrossRef][Green Version]
  10. Heindel, J.J.; Vandenberg, L.N. Developmental origins of health and disease: A paradigm for understanding disease etiology and prevention. Curr. Opin. Pediatrics 2015, 27, 248. [Google Scholar] [CrossRef][Green Version]
  11. Painter, R.C.; Roseboom, T.J.; Van Montfrans, G.A.; Bossuyt, P.M.; Krediet, R.T.; Osmond, C.; Barker, D.J.; Bleker, O.P. Microalbuminuria in adults after prenatal exposure to the Dutch famine. J. Am. Soc. Nephrol. 2005, 16, 189–194. [Google Scholar] [CrossRef]
  12. Lopuhaä, C.; Roseboom, T.; Osmond, C.; Barker, D.; Ravelli, A.; Bleker, O.; Van Der Zee, J.; Van Der Meulen, J. Atopy, lung function, and obstructive airways disease after prenatal exposure to famine. Thorax 2000, 55, 555–561. [Google Scholar] [CrossRef][Green Version]
  13. Kim, D.R.; Bale, T.L.; Epperson, C.N. Prenatal programming of mental illness: Current understanding of relationship and mechanisms. Curr. Psychiatry Rep. 2015, 17, 5. [Google Scholar] [CrossRef][Green Version]
  14. Roseboom, T.J.; van der Meulen, J.H.; Osmond, C.; Barker, D.J.; Ravelli, A.C.; Bleker, O.P. Plasma lipid profiles in adults after prenatal exposure to the Dutch famine. Am. J. Clin. Nutr. 2000, 72, 1101–1106. [Google Scholar] [CrossRef][Green Version]
  15. Kyle, U.G.; Pichard, C. The Dutch Famine of 1944–1945: A pathophysiological model of long-term consequences of wasting disease. Curr. Opin. Clin. Nutr. Metab. Care 2006, 9, 388–394. [Google Scholar] [CrossRef]
  16. Schmutte, C.; Jones, P.A. Involvement of DNA methylation in human carcinogenesis. Biol. Chem. 1998, 379, 377–388. [Google Scholar]
  17. Williams, K.T.; Garrow, T.A.; Schalinske, K.L. Type I diabetes leads to tissue-specific DNA hypomethylation in male rats. J. Nutr. 2008, 138, 2064–2069. [Google Scholar] [CrossRef][Green Version]
  18. Bogdarina, I.; Welham, S.; King, P.J.; Burns, S.P.; Clark, A.J. Epigenetic modification of the renin-angiotensin system in the fetal programming of hypertension. Circ. Res. 2007, 100, 520–526. [Google Scholar] [CrossRef][Green Version]
  19. Goyal, R.; Galffy, A.; Field, S.A.; Gheorghe, C.P.; Mittal, A.; Longo, L.D. Maternal protein deprivation: Changes in systemic renin-angiotensin system of the mouse fetus. Reprod. Sci. 2009, 16, 894–904. [Google Scholar] [CrossRef]
  20. Goyal, R.; Longo, L.D. Maternal protein deprivation: Sexually dimorphic programming of hypertension in the mouse. Hypertens. Res. 2013, 36, 29–35. [Google Scholar] [CrossRef][Green Version]
  21. Obeid, R.; Schadt, A.; Dillmann, U.; Kostopoulos, P.; Fassbender, K.; Herrmann, W. Methylation status and neurodegenerative markers in Parkinson disease. Clin. Chem. 2009, 55, 1852–1860. [Google Scholar] [CrossRef][Green Version]
  22. Goyal, R.; Goyal, D.; Leitzke, A.; Gheorghe, C.P.; Longo, L.D. Brain renin-angiotensin system: Fetal epigenetic programming by maternal protein restriction during pregnancy. Reprod. Sci. 2010, 17, 227–238. [Google Scholar] [CrossRef] [PubMed]
  23. Goyal, R.; Goyal, D.; Chu, N.; Van Wickle, J.; Longo, L.D. Cerebral artery alpha-1 AR subtypes: High altitude long-term acclimatization responses. PLoS ONE 2014, 9, e112784. [Google Scholar] [CrossRef] [PubMed][Green Version]
  24. Ducsay, C.A.; Goyal, R.; Pearce, W.J.; Wilson, S.; Hu, X.-Q.; Zhang, L. Gestational hypoxia and developmental plasticity. Physiol. Rev. 2018, 98, 1241–1334. [Google Scholar] [CrossRef] [PubMed]
  25. Aizer, A.; Stroud, L.; Buka, S. Maternal stress and child outcomes: Evidence from siblings. J. Hum. Resour. 2016, 51, 523–555. [Google Scholar] [CrossRef]
  26. Christian, L.M. Stress and immune function during pregnancy: An emerging focus in mind-body medicine. Curr. Dir. Psychol. Sci. 2015, 24, 3–9. [Google Scholar] [CrossRef]
  27. Huizink, A.; Menting, B.; Oosterman, M.; Verhage, M.; Kunseler, F.; Schuengel, C. The interrelationship between pregnancy-specific anxiety and general anxiety across pregnancy: A longitudinal study. J. Psychosom. Obstet. Gynecol. 2014, 35, 92–100. [Google Scholar] [CrossRef]
  28. Kinsella, M.T.; Monk, C. Impact of maternal stress, depression & anxiety on fetal neurobehavioral development. Clin. Obstet. Gynecol. 2009, 52, 425. [Google Scholar]
  29. Mulder, E.J.; De Medina, P.R.; Huizink, A.C.; Van den Bergh, B.R.; Buitelaar, J.K.; Visser, G.H. Prenatal maternal stress: Effects on pregnancy and the (unborn) child. Early Hum. Dev. 2002, 70, 3–14. [Google Scholar] [CrossRef]
  30. Vehmeijer, F.O.; Guxens, M.; Duijts, L.; El Marroun, H. Maternal psychological distress during pregnancy and childhood health outcomes: A narrative review. J. Dev. Orig. Health Dis. 2019, 10, 274–285. [Google Scholar] [CrossRef][Green Version]
  31. Skodol, A.E.; Shrout, P.E. Use of DSM-III axis IV in clinical practice: Rating etiologically significant stressors. Am. J. Psychiatry 1989, 146, 61–66. [Google Scholar]
  32. Leach, L.S.; Poyser, C.; Fairweather-Schmidt, K. Maternal perinatal anxiety: A review of prevalence and correlates. Clin. Psychol. 2017, 21, 4–19. [Google Scholar] [CrossRef]
  33. Melville, J.L.; Gavin, A.; Guo, Y.; Fan, M.-Y.; Katon, W.J. Depressive disorders during pregnancy: Prevalence and risk factors in a large urban sample. Obstet. Gynecol. 2010, 116, 1064. [Google Scholar] [CrossRef][Green Version]
  34. Woods, S.M.; Melville, J.L.; Guo, Y.; Fan, M.-Y.; Gavin, A. Psychosocial stress during pregnancy. Am. J. Obstet. Gynecol. 2010, 202, 61.e1-61.e7. [Google Scholar] [CrossRef]
  35. Rees, S.; Channon, S.; Waters, C.S. The impact of maternal prenatal and postnatal anxiety on children’s emotional problems: A systematic review. Eur. Child Adolesc. Psychiatry 2019, 28, 257–280. [Google Scholar] [CrossRef][Green Version]
  36. Quinlivan, J.; Lambregtse-van den Berg, M. Will COVID-19 Impact upon Pregnancy, Childhood and Adult Outcomes? A Call to Establish National Longitudinal Datasets; Taylor & Francis: Abingdon, UK, 2020; Volume 41, pp. 165–166. [Google Scholar]
  37. Berthelot, N.; Lemieux, R.; Garon-Bissonnette, J.; Drouin-Maziade, C.; Martel, É.; Maziade, M. Uptrend in distress and psychiatric symptomatology in pregnant women during the coronavirus disease 2019 pandemic. Acta Obstet. Et Gynecol. Scand. 2020, 99, 848–855. [Google Scholar] [CrossRef]
  38. Lebel, C.; MacKinnon, A.; Bagshawe, M.; Tomfohr-Madsen, L.; Giesbrecht, G. Elevated depression and anxiety symptoms among pregnant individuals during the COVID-19 pandemic. J. Affect. Disord. 2020, 277, 5–13. [Google Scholar] [CrossRef]
  39. Preis, H.; Mahaffey, B.; Heiselman, C.; Lobel, M. Pandemic-related pregnancy stress and anxiety among women pregnant during the coronavirus disease 2019 pandemic. Am. J. Obstet. Gynecol. MFM 2020, 2, 100155. [Google Scholar] [CrossRef]
  40. Yue, C.; Liu, C.; Wang, J.; Zhang, M.; Wu, H.; Li, C.; Yang, X. Association between social support and anxiety among pregnant women in the third trimester during the coronavirus disease 2019 (COVID-19) epidemic in Qingdao, China: The mediating effect of risk perception. Int. J. Soc. Psychiatry 2021, 67, 120–127. [Google Scholar] [CrossRef]
  41. Omowale, S.S.; Casas, A.; Lai, Y.-H.; Sanders, S.A.; Hill, A.V.; Wallace, M.L.; Rathbun, S.L.; Gary-Webb, T.L.; Burke, L.E.; Davis, E.M. Trends in stress throughout pregnancy and postpartum period during the COVID-19 pandemic: Longitudinal study using ecological momentary assessment and data from the Postpartum Mothers Mobile Study. JMIR Ment. Health 2021, 8, e30422. [Google Scholar] [CrossRef]
  42. Barker, D.J. The developmental origins of adult disease. Eur. J. Epidemiol. 2003, 23, 733–736. [Google Scholar] [CrossRef]
  43. Nugent, B.M.; Bale, T.L. The omniscient placenta: Metabolic and epigenetic regulation of fetal programming. Front. Neuroendocrinol. 2015, 39, 28–37. [Google Scholar] [CrossRef] [PubMed][Green Version]
  44. Yehuda, R.; Lehrner, A. Intergenerational transmission of trauma effects: Putative role of epigenetic mechanisms. World Psychiatry 2018, 17, 243–257. [Google Scholar] [CrossRef] [PubMed][Green Version]
  45. Rakers, F.; Rupprecht, S.; Dreiling, M.; Bergmeier, C.; Witte, O.W.; Schwab, M. Transfer of maternal psychosocial stress to the fetus. Neurosci. Biobehav. Rev. 2020, 117, 185–197. [Google Scholar] [CrossRef] [PubMed]
  46. Matas-Blanco, C.; Caparros-Gonzalez, R.A. Influence of maternal stress during pregnancy on child’s neurodevelopment. Psych 2020, 2, 16. [Google Scholar] [CrossRef]
  47. Cao-Lei, L.; van den Heuvel, M.I.; Huse, K.; Platzer, M.; Elgbeili, G.; Braeken, M.A.; Otte, R.A.; Witte, O.W.; Schwab, M.; Van den Bergh, B.R. Epigenetic modifications associated with maternal anxiety during pregnancy and children’s behavioral measures. Cells 2021, 10, 2421. [Google Scholar] [CrossRef]
  48. Veru, F.; Laplante, D.P.; Luheshi, G.; King, S. Prenatal maternal stress exposure and immune function in the offspring. Stress 2014, 17, 133–148. [Google Scholar] [CrossRef]
  49. Graignic-Philippe, R.; Dayan, J.; Chokron, S.; Jacquet, A.; Tordjman, S. Effects of prenatal stress on fetal and child development: A critical literature review. Neurosci. Biobehav. Rev. 2014, 43, 137–162. [Google Scholar] [CrossRef]
  50. Oberlander, T.F.; Weinberg, J.; Papsdorf, M.; Grunau, R.; Misri, S.; Devlin, A.M. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 2008, 3, 97–106. [Google Scholar] [CrossRef][Green Version]
  51. Van den Bergh, B.R.; van den Heuvel, M.I.; Lahti, M.; Braeken, M.; de Rooij, S.R.; Entringer, S.; Hoyer, D.; Roseboom, T.; Räikkönen, K.; King, S. Prenatal developmental origins of behavior and mental health: The influence of maternal stress in pregnancy. Neurosci. Biobehav. Rev. 2020, 117, 26–64. [Google Scholar] [CrossRef][Green Version]
  52. Mueller, B.R.; Bale, T.L. Sex-specific programming of offspring emotionality after stress early in pregnancy. J. Neurosci. 2008, 28, 9055–9065. [Google Scholar] [CrossRef][Green Version]
  53. Carpenter, T.; Grecian, S.; Reynolds, R. Sex differences in early-life programming of the hypothalamic–Pituitary–Adrenal axis in humans suggest increased vulnerability in females: A systematic review. J. Dev. Orig. Health Dis. 2017, 8, 244–255. [Google Scholar] [CrossRef][Green Version]
  54. Mansell, T.; Novakovic, B.; Meyer, B.; Rzehak, P.; Vuillermin, P.; Ponsonby, A.; Collier, F.; Burgner, D.; Saffery, R.; Ryan, J. The effects of maternal anxiety during pregnancy on IGF2/H19 methylation in cord blood. Transl. Psychiatry 2016, 6, e765. [Google Scholar] [CrossRef][Green Version]
  55. Appleton, A.A.; Armstrong, D.A.; Lesseur, C.; Lee, J.; Padbury, J.F.; Lester, B.M.; Marsit, C.J. Patterning in placental 11-B hydroxysteroid dehydrogenase methylation according to prenatal socioeconomic adversity. PLoS ONE 2013, 8, e74691. [Google Scholar] [CrossRef]
  56. Stroud, L.R.; Papandonatos, G.D.; Parade, S.H.; Salisbury, A.L.; Phipps, M.G.; Lester, B.; Padbury, J.F.; Marsit, C.J. Prenatal major depressive disorder, placenta glucocorticoid and serotonergic signaling, and infant cortisol response. Psychosom. Med. 2016, 78, 979. [Google Scholar] [CrossRef]
  57. Ostlund, B.D.; Conradt, E.; Crowell, S.E.; Tyrka, A.R.; Marsit, C.J.; Lester, B.M. Prenatal stress, fearfulness, and the epigenome: Exploratory analysis of sex differences in DNA methylation of the glucocorticoid receptor gene. Front. Behav. Neurosci. 2016, 10, 147. [Google Scholar] [CrossRef][Green Version]
  58. Braithwaite, E.; Kundakovic, M.; Ramchandani, P.; Murphy, S.; Champagne, F. Maternal prenatal depressive symptoms predict infant NR3C1 1F and BDNF IV DNA methylation. Epigenetics 2015, 10, 408–417. [Google Scholar] [CrossRef][Green Version]
  59. Kemeny, M.E. The psychobiology of stress. Curr. Dir. Psychol. Sci. 2003, 12, 124–129. [Google Scholar] [CrossRef]
  60. Najafzadeh, A. Stress and preterm birth: Biological and vascular mechanisms affecting the feto-placental circulation and the length of gestation. Sonography 2016, 3, 95–102. [Google Scholar] [CrossRef]
  61. Sheng, J.A.; Bales, N.J.; Myers, S.A.; Bautista, A.I.; Roueinfar, M.; Hale, T.M.; Handa, R.J. The hypothalamic-pituitary-adrenal axis: Development, programming actions of hormones, and maternal-fetal interactions. Front. Behav. Neurosci. 2021, 14, 601939. [Google Scholar] [CrossRef]
  62. Hobel, C.J.; Goldstein, A.; Barrett, E.S. Psychosocial stress and pregnancy outcome. Clin. Obstet. Gynecol. 2008, 51, 333–348. [Google Scholar] [CrossRef]
  63. Benfield, R.D.; Newton, E.R.; Tanner, C.J.; Heitkemper, M.M. Cortisol as a biomarker of stress in term human labor: Physiological and methodological issues. Biol. Res. Nurs. 2014, 16, 64–71. [Google Scholar] [CrossRef] [PubMed][Green Version]
  64. Wood, C.E.; Keller-Wood, M. The critical importance of the fetal hypothalamus-pituitary-adrenal axis. F1000Research 2016, 5, F1000. [Google Scholar] [CrossRef] [PubMed][Green Version]
  65. Dusek, J.A.; Benson, H. Mind-body medicine: A model of the comparative clinical impact of the acute stress and relaxation responses. Minn. Med. 2009, 92, 47. [Google Scholar] [PubMed]
  66. Anifantaki, F.; Pervanidou, P.; Lambrinoudaki, I.; Panoulis, K.; Vlahos, N.; Eleftheriades, M. Maternal prenatal stress, thyroid function and neurodevelopment of the offspring: A mini review of the literature. Front. Neurosci. 2021, 15, 692446. [Google Scholar] [CrossRef] [PubMed]
  67. Lizcano, F.; Rodríguez, J.S. Thyroid hormone therapy modulates hypothalamo-pituitary-adrenal axis. Endocr. J. 2011, 58, 137–142. [Google Scholar] [CrossRef][Green Version]
  68. Lautarescu, A.; Craig, M.C.; Glover, V. Prenatal stress: Effects on fetal and child brain development. Int. Rev. Neurobiol. 2020, 150, 17–40. [Google Scholar]
  69. Glover, V.; O’Donnell, K.J.; O’Connor, T.G.; Fisher, J. Prenatal maternal stress, fetal programming, and mechanisms underlying later psychopathology—A global perspective. Dev. Psychopathol. 2018, 30, 843–854. [Google Scholar] [CrossRef]
  70. Martinez, C.A.; Marteinsdottir, I.; Josefsson, A.; Sydsjö, G.; Theodorsson, E.; Rodriguez-Martinez, H. Expression of stress-mediating genes is increased in term placentas of women with chronic self-perceived anxiety and depression. Genes 2020, 11, 869. [Google Scholar] [CrossRef]
  71. Charil, A.; Laplante, D.P.; Vaillancourt, C.; King, S. Prenatal stress and brain development. Brain Res. Rev. 2010, 65, 56–79. [Google Scholar] [CrossRef]
  72. Seckl, J.R.; Holmes, M.C. Mechanisms of disease: Glucocorticoids, their placental metabolism and fetal ’programming’ of adult pathophysiology. Nat. Clin. Pract. Endocrinol. Metab. 2007, 3, 479–488. [Google Scholar] [CrossRef]
  73. Ryan, J.; Mansell, T.; Fransquet, P.; Saffery, R. Does maternal mental well-being in pregnancy impact the early human epigenome? Epigenomics 2017, 9, 313–332. [Google Scholar] [CrossRef]
  74. Shallie, P.D.; Naicker, T. The placenta as a window to the brain: A review on the role of placental markers in prenatal programming of neurodevelopment. Int. J. Dev. Neurosci. 2019, 73, 41–49. [Google Scholar] [CrossRef]
  75. Lin, Y.; Xu, J.; Huang, J.; Jia, Y.; Zhang, J.; Yan, C.; Zhang, J. Effects of prenatal and postnatal maternal emotional stress on toddlers’ cognitive and temperamental development. J. Affect. Disord. 2017, 207, 9–17. [Google Scholar] [CrossRef] [PubMed]
  76. Wadhwa, P.D.; Entringer, S.; Buss, C.; Lu, M.C. The contribution of maternal stress to preterm birth: Issues and considerations. Clin. Perinatol. 2011, 38, 351–384. [Google Scholar] [CrossRef] [PubMed]
  77. Zhang, W.; Li, Q.; Deyssenroth, M.; Lambertini, L.; Finik, J.; Ham, J.; Huang, Y.; Tsuchiya, K.J.; Pehme, P.; Buthmann, J. Timing of prenatal exposure to trauma and altered placental expressions of hypothalamic-pituitary-adrenal axis genes and genes driving neurodevelopment. J. Neuroendocrinol. 2018, 30, e12581. [Google Scholar] [CrossRef]
  78. Ruffaner-Hanson, C.; Noor, S.; Sun, M.S.; Solomon, E.; Marquez, L.E.; Rodriguez, D.E.; Allan, A.M.; Caldwell, K.K.; Bakhireva, L.N.; Milligan, E.D. The maternal-placental-fetal interface: Adaptations of the HPA axis and immune mediators following maternal stress and prenatal alcohol exposure. Exp. Neurol. 2022, 355, 114121. [Google Scholar] [CrossRef] [PubMed]
  79. Kosicka, K.; Siemiątkowska, A.; Główka, F.K. 11β-Hydroxysteroid dehydrogenase 2 in preeclampsia. Int. J. Endocrinol. 2016, 2016, 5279462. [Google Scholar] [CrossRef][Green Version]
  80. O’Donnell, K.J.; Jensen, A.B.; Freeman, L.; Khalife, N.; O’Connor, T.G.; Glover, V. Maternal prenatal anxiety and downregulation of placental 11β-HSD2. Psychoneuroendocrinology 2012, 37, 818–826. [Google Scholar] [CrossRef]
  81. Togher, K.L.; Treacy, E.; O’Keeffe, G.W.; Kenny, L.C. Maternal distress in late pregnancy alters obstetric outcomes and the expression of genes important for placental glucocorticoid signalling. Psychiatry Res. 2017, 255, 17–26. [Google Scholar] [CrossRef]
  82. Coussons-Read, M.E.; Okun, M.L.; Nettles, C.D. Psychosocial stress increases inflammatory markers and alters cytokine production across pregnancy. Brain Behav. Immun. 2007, 21, 343–350. [Google Scholar] [CrossRef]
  83. Karlsson, L.; Nousiainen, N.; Scheinin, N.M.; Maksimow, M.; Salmi, M.; Lehto, S.M.; Tolvanen, M.; Lukkarinen, H.; Karlsson, H. Cytokine profile and maternal depression and anxiety symptoms in mid-pregnancy—The FinnBrain Birth Cohort Study. Arch. Women’s Ment. Health 2017, 20, 39–48. [Google Scholar] [CrossRef]
  84. Glover, V. Prenatal stress and its effects on the fetus and the child: Possible underlying biological mechanisms. In Perinatal Programming of Neurodevelopment; Springer: Berlin/Heidelberg, Germany, 2015; pp. 269–283. [Google Scholar]
  85. Raghupathy, R.; Kalinka, J. Cytokine imbalance in pregnancy complications and its modulation. Front. Biosci. -Landmark 2008, 13, 985–994. [Google Scholar] [CrossRef][Green Version]
  86. Aaltonen, R.; Heikkinen, T.; Hakala, K.; Laine, K.; Alanen, A. Transfer of proinflammatory cytokines across term placenta. Obstet. Gynecol. 2005, 106, 802–807. [Google Scholar] [CrossRef]
  87. Izvolskaia, M.; Sharova, V.; Zakharova, L. Prenatal programming of neuroendocrine system development by lipopolysaccharide: Long-term effects. Int. J. Mol. Sci. 2018, 19, 3695. [Google Scholar] [CrossRef]
  88. Cory-Slechta, D.A. Enduring Behavioral and Brain Impacts of Prenatal Stress and Childhood Adversity and Their Potential Multigenerational Consequences. In Advances in Neurotoxicology; Elsevier: Amsterdam, The Netherlands, 2018; Volume 2, pp. 265–300. [Google Scholar]
  89. St-Pierre, J.; Laurent, L.; King, S.; Vaillancourt, C. Effects of prenatal maternal stress on serotonin and fetal development. Placenta 2016, 48, S66–S71. [Google Scholar] [CrossRef]
  90. Entringer, S.; Buss, C.; Rasmussen, J.M.; Lindsay, K.; Gillen, D.L.; Cooper, D.M.; Wadhwa, P.D. Maternal cortisol during pregnancy and infant adiposity: A prospective investigation. J. Clin. Endocrinol. Metab. 2017, 102, 1366–1374. [Google Scholar] [CrossRef]
  91. Blakeley, P.M.; Capron, L.E.; Jensen, A.B.; O’Donnell, K.J.; Glover, V. Maternal prenatal symptoms of depression and down regulation of placental monoamine oxidase A expression. J. Psychosom. Res. 2013, 75, 341–345. [Google Scholar] [CrossRef]
  92. Bonnin, A.; Levitt, P. Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain. Neuroscience 2011, 197, 1–7. [Google Scholar] [CrossRef][Green Version]
  93. Szumiel, I. Ionizing radiation-induced oxidative stress, epigenetic changes and genomic instability: The pivotal role of mitochondria. Int. J. Radiat. Biol. 2015, 91, 1–12. [Google Scholar] [CrossRef]
  94. Niu, Y.; DesMarais, T.L.; Tong, Z.; Yao, Y.; Costa, M. Oxidative stress alters global histone modification and DNA methylation. Free. Radic. Biol. Med. 2015, 82, 22–28. [Google Scholar] [CrossRef][Green Version]
  95. Jašarević, E.; Rodgers, A.B.; Bale, T.L. A novel role for maternal stress and microbial transmission in early life programming and neurodevelopment. Neurobiol. Stress 2015, 1, 81–88. [Google Scholar] [CrossRef] [PubMed][Green Version]
  96. Talarowska, M. Epigenetic mechanisms in the neurodevelopmental theory of depression. Depress. Res. Treat. 2020, 2020, 6357873. [Google Scholar] [CrossRef] [PubMed]
  97. Hoffmann, A.; Spengler, D. Environmental factors and epigenetics of neuropsychiatric disorders. In Neuropsychiatric Disorders and Epigenetics; Elsevier: Amsterdam, The Netherlands, 2017; pp. 9–33. [Google Scholar]
  98. Cao-Lei, L.; De Rooij, S.; King, S.; Matthews, S.; Metz, G.; Roseboom, T.; Szyf, M. Prenatal stress and epigenetics. Neurosci. Biobehav. Rev. 2020, 117, 198–210. [Google Scholar] [CrossRef] [PubMed]
  99. Šerman, A.; Vlahović, M.; Šerman, L.; Bulić-Jakuš, F. DNA methylation as a regulatory mechanism for gene expression in mammals. Coll. Antropol. 2006, 30, 665–671. [Google Scholar] [PubMed]
  100. Shimada-Sugimoto, M.; Otowa, T.; Hettema, J.M. Genetics of anxiety disorders: Genetic epidemiological and molecular studies in humans. Psychiatry Clin. Neurosci. 2015, 69, 388–401. [Google Scholar] [CrossRef]
  101. Conradt, E.; Lester, B.M.; Appleton, A.A.; Armstrong, D.A.; Marsit, C.J. The roles of DNA methylation of NR3C1 and 11β-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics 2013, 8, 1321–1329. [Google Scholar] [CrossRef][Green Version]
  102. Hompes, T.; Izzi, B.; Gellens, E.; Morreels, M.; Fieuws, S.; Pexsters, A.; Schops, G.; Dom, M.; Van Bree, R.; Freson, K. Investigating the influence of maternal cortisol and emotional state during pregnancy on the DNA methylation status of the glucocorticoid receptor gene (NR3C1) promoter region in cord blood. J. Psychiatr. Res. 2013, 47, 880–891. [Google Scholar] [CrossRef]
  103. Mansell, T.; Vuillermin, P.; Ponsonby, A.-L.; Collier, F.; Saffery, R.; Ryan, J. Maternal mental well-being during pregnancy and glucocorticoid receptor gene promoter methylation in the neonate. Dev. Psychopathol. 2016, 28, 1421–1430. [Google Scholar] [CrossRef][Green Version]
  104. Monk, C.; Feng, T.; Lee, S.; Krupska, I.; Champagne, F.A.; Tycko, B. Distress during pregnancy: Epigenetic regulation of placenta glucocorticoid-related genes and fetal neurobehavior. Am. J. Psychiatry 2016, 173, 705–713. [Google Scholar] [CrossRef][Green Version]
  105. Marsit, C.J.; Maccani, M.A.; Padbury, J.F.; Lester, B.M. Placental 11-beta hydroxysteroid dehydrogenase methylation is associated with newborn growth and a measure of neurobehavioral outcome. PLoS ONE 2012, 7, e33794. [Google Scholar] [CrossRef][Green Version]
  106. Devlin, A.M.; Brain, U.; Austin, J.; Oberlander, T.F. Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth. PLoS ONE 2010, 5, e12201. [Google Scholar] [CrossRef][Green Version]
  107. Sosnowski, D.W.; Booth, C.; York, T.P.; Amstadter, A.B.; Kliewer, W. Maternal prenatal stress and infant DNA methylation: A systematic review. Dev. Psychobiol. 2018, 60, 127–139. [Google Scholar] [CrossRef]
  108. Chen, J.; Li, Q.; Rialdi, A.; Mystal, E.; Ly, J.; Finik, J.; Davey, T.; Lambertini, L.; Nomura, Y. Influences of maternal stress during pregnancy on the epi/genome: Comparison of placenta and umbilical cord blood. J. Depress. Anxiety 2014, 3, 152. [Google Scholar]
  109. Bannister, A.J.; Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 2011, 21, 381–395. [Google Scholar] [CrossRef]
  110. Seo, M.K.; Kim, S.-g.; Seog, D.-H.; Bahk, W.-M.; Kim, S.-H.; Park, S.W.; Lee, J.G. Effects of early life stress on epigenetic changes of the glucocorticoid receptor 17 promoter during adulthood. Int. J. Mol. Sci. 2020, 21, 6331. [Google Scholar] [CrossRef]
  111. Deussing, J.M.; Jakovcevski, M. Histone modifications in major depressive disorder and related rodent models. Neuroepigenomics Aging Dis. 2017, 978, 169–183. [Google Scholar]
  112. Kumar, S.; Gonzalez, E.A.; Rameshwar, P.; Etchegaray, J.-P. Non-coding RNAs as mediators of epigenetic changes in malignancies. Cancers 2020, 12, 3657. [Google Scholar] [CrossRef]
  113. Miguel, V.; Lamas, S.; Espinosa-Diez, C. Role of non-coding-RNAs in response to environmental stressors and consequences on human health. Redox Biol. 2020, 37, 101580. [Google Scholar] [CrossRef]
  114. Ding, X.-X.; Wu, Y.-L.; Xu, S.-J.; Zhu, R.-P.; Jia, X.-M.; Zhang, S.-F.; Huang, K.; Zhu, P.; Hao, J.-H.; Tao, F.-B. Maternal anxiety during pregnancy and adverse birth outcomes: A systematic review and meta-analysis of prospective cohort studies. J. Affect. Disord. 2014, 159, 103–110. [Google Scholar] [CrossRef]
  115. Troller-Renfree, S.V.; Brito, N.H.; Desai, P.M.; Leon-Santos, A.G.; Wiltshire, C.A.; Motton, S.N.; Meyer, J.S.; Isler, J.; Fifer, W.P.; Noble, K.G. Infants of mothers with higher physiological stress show alterations in brain function. Dev. Sci. 2020, 23, e12976. [Google Scholar] [CrossRef]
  116. Buss, C.; Davis, E.P.; Muftuler, L.T.; Head, K.; Sandman, C.A. High pregnancy anxiety during mid-gestation is associated with decreased gray matter density in 6–9-year-old children. Psychoneuroendocrinology 2010, 35, 141–153. [Google Scholar] [CrossRef] [PubMed][Green Version]
  117. Wu, Y.; Lu, Y.-C.; Jacobs, M.; Pradhan, S.; Kapse, K.; Zhao, L.; Niforatos-Andescavage, N.; Vezina, G.; du Plessis, A.J.; Limperopoulos, C. Association of prenatal maternal psychological distress with fetal brain growth, metabolism, and cortical maturation. JAMA Netw. Open 2020, 3, e1919940. [Google Scholar] [CrossRef] [PubMed][Green Version]
  118. Mikšić, Š.; Uglešić, B.; Jakab, J.; Holik, D.; Milostić Srb, A.; Degmečić, D. Positive effect of breastfeeding on child development, anxiety, and postpartum depression. Int. J. Environ. Res. Public Health 2020, 17, 2725. [Google Scholar] [CrossRef] [PubMed][Green Version]
  119. Di Benedetto, M.G.; Bottanelli, C.; Cattaneo, A.; Pariante, C.M.; Borsini, A. Nutritional and immunological factors in breast milk: A role in the intergenerational transmission from maternal psychopathology to child development. Brain Behav. Immun. 2020, 85, 57–68. [Google Scholar] [CrossRef] [PubMed]
  120. Serim Demirgoren, B.; Ozbek, A.; Ormen, M.; Kavurma, C.; Ozer, E.; Aydın, A. Do mothers with high sodium levels in their breast milk have high depression and anxiety scores? J. Int. Med. Res. 2017, 45, 843–848. [Google Scholar] [CrossRef]
  121. Kim, J.-H.; Shin, H.-S.; Lee, W.-H. Impact of endocrine-disrupting chemicals in breast milk on postpartum depression in Korean mothers. Int. J. Environ. Res. Public Health 2021, 18, 4444. [Google Scholar] [CrossRef]
  122. Shariat, M.; Abedinia, N.; Rezaei, N.; Farrokhzad, N. Increase concentration of transforming growth factor beta (TGF-β) in breast milk of mothers with psychological disorders. Acta Med. Iran. 2017, 55, 429–436. [Google Scholar]
  123. Kang, L.J.; Koleva, P.T.; Field, C.J.; Giesbrecht, G.F.; Wine, E.; Becker, A.B.; Mandhane, P.J.; Turvey, S.E.; Subbarao, P.; Sears, M.R. Maternal depressive symptoms linked to reduced fecal Immunoglobulin A concentrations in infants. Brain Behav. Immun. 2018, 68, 123–131. [Google Scholar] [CrossRef]
  124. Kawano, A.; Emori, Y. The relationship between maternal postpartum psychological state and breast milk secretory immunoglobulin A level. J. Am. Psychiatr. Nurses Assoc. 2015, 21, 23–30. [Google Scholar] [CrossRef][Green Version]
  125. Moirasgenti, M.; Doulougeri, K.; Panagopoulou, E.; Theodoridis, T. Psychological stress reduces the immunological benefits of breast milk. Stress Health 2019, 35, 681–685. [Google Scholar] [CrossRef]
  126. Aparicio, M.; Browne, P.D.; Hechler, C.; Beijers, R.; Rodríguez, J.M.; de Weerth, C.; Fernández, L. Human milk cortisol and immune factors over the first three postnatal months: Relations to maternal psychosocial distress. PLoS ONE 2020, 15, e0233554. [Google Scholar] [CrossRef]
  127. Ziomkiewicz, A.; Apanasewicz, A.; Danel, D.P.; Babiszewska, M.; Piosek, M.; Orczyk-Pawiłowicz, M. Maternal distress and social support are linked to human milk immune properties. Nutrients 2021, 13, 1857. [Google Scholar] [CrossRef]
  128. Lauritzen, L.a. The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina. Prog. Lipid Res. 2001, 40, 1–94. [Google Scholar] [CrossRef]
  129. Keim, S.A.; Daniels, J.L.; Siega-Riz, A.M.; Dole, N.; Herring, A.H.; Scheidt, P.C. Depressive symptoms during pregnancy and the concentration of fatty acids in breast milk. J. Hum. Lact. 2012, 28, 189–195. [Google Scholar] [CrossRef]
  130. Ziomkiewicz, A.; Babiszewska, M.; Apanasewicz, A.; Piosek, M.; Wychowaniec, P.; Cierniak, A.; Barbarska, O.; Szołtysik, M.; Danel, D.; Wichary, S. Psychosocial stress and cortisol stress reactivity predict breast milk composition. Sci. Rep. 2021, 11, 11576. [Google Scholar] [CrossRef]
  131. Abou-Saleh, M.T.; Ghubash, R.; Karim, L.; Krymski, M.; Bhai, I. Hormonal aspects of postpartum depression. Psychoneuroendocrinology 1998, 23, 465–475. [Google Scholar] [CrossRef]
  132. Stuebe, A.M.; Grewen, K.; Meltzer-Brody, S. Association between maternal mood and oxytocin response to breastfeeding. J. Women’s Health 2013, 22, 352–361. [Google Scholar] [CrossRef]
  133. Vass, R.A.; Kiss, G.; Bell, E.F.; Roghair, R.D.; Miseta, A.; Bódis, J.; Funke, S.; Ertl, T. Breast Milk for Term and Preterm Infants—Own Mother’s Milk or Donor Milk? Nutrients 2021, 13, 424. [Google Scholar] [CrossRef]
  134. De Weerth, C.; Aatsinki, A.-K.; Azad, M.B.; Bartol, F.F.; Bode, L.; Collado, M.C.; Dettmer, A.M.; Field, C.J.; Guilfoyle, M.; Hinde, K. Human milk: From complex tailored nutrition to bioactive impact on child cognition and behavior. Crit. Rev. Food Sci. Nutr. 2022, 1–38. [Google Scholar] [CrossRef]
  135. Kortesniemi, M.; Slupsky, C.M.; Aatsinki, A.-K.; Sinkkonen, J.; Karlsson, L.; Linderborg, K.M.; Yang, B.; Karlsson, H.; Kailanto, H.-M. Human milk metabolome is associated with symptoms of maternal psychological distress and milk cortisol. Food Chem. 2021, 356, 129628. [Google Scholar] [CrossRef]
  136. Newman, L.; Sivaratnam, C.; Komiti, A. Attachment and early brain development–neuroprotective interventions in infant–Caregiver therapy. Transl. Dev. Psychiatry 2015, 3, 28647. [Google Scholar] [CrossRef][Green Version]
  137. Cooke, J.E.; Racine, N.; Plamondon, A.; Tough, S.; Madigan, S. Maternal adverse childhood experiences, attachment style, and mental health: Pathways of transmission to child behavior problems. Child Abus. Negl. 2019, 93, 27–37. [Google Scholar] [CrossRef] [PubMed]
  138. Provençal, N.; Binder, E.B. The effects of early life stress on the epigenome: From the womb to adulthood and even before. Exp. Neurol. 2015, 268, 10–20. [Google Scholar] [CrossRef] [PubMed]
  139. Weaver, I.C.; Cervoni, N.; Champagne, F.A.; D’Alessio, A.C.; Sharma, S.; Seckl, J.R.; Dymov, S.; Szyf, M.; Meaney, M.J. Epigenetic programming by maternal behavior. Nat. Neurosci. 2004, 7, 847–854. [Google Scholar] [CrossRef]
  140. Blackmore, E.R.; Gustafsson, H.; Gilchrist, M.; Wyman, C.; O’Connor, T.G. Pregnancy-related anxiety: Evidence of distinct clinical significance from a prospective longitudinal study. J. Affect. Disord. 2016, 197, 251–258. [Google Scholar] [CrossRef][Green Version]
  141. Ibanez, G.; Charles, M.-A.; Forhan, A.; Magnin, G.; Thiebaugeorges, O.; Kaminski, M.; Saurel-Cubizolles, M.-J.; Group, E.M.C.C.S. Depression and anxiety in women during pregnancy and neonatal outcome: Data from the EDEN mother–child cohort. Early Hum. Dev. 2012, 88, 643–649. [Google Scholar] [CrossRef]
  142. Lobel, M.; Cannella, D.L.; Graham, J.E.; DeVincent, C.; Schneider, J.; Meyer, B.A. Pregnancy-specific stress, prenatal health behaviors, and birth outcomes. Health Psychol. 2008, 27, 604. [Google Scholar] [CrossRef]
  143. Rifkin-Graboi, A.; Meaney, M.J.; Chen, H.; Bai, J.; Hameed, W.B.r.; Tint, M.T.; Broekman, B.F.; Chong, Y.-S.; Gluckman, P.D.; Fortier, M.V. Antenatal maternal anxiety predicts variations in neural structures implicated in anxiety disorders in newborns. J. Am. Acad. Child Adolesc. Psychiatry 2015, 54, 313–321 e2. [Google Scholar] [CrossRef]
  144. King, S.; Dancause, K.; Turcotte-Tremblay, A.M.; Veru, F.; Laplante, D.P. Using natural disasters to study the effects of prenatal maternal stress on child health and development. Birth Defects Res. Part C Embryo Today Rev. 2012, 96, 273–288. [Google Scholar] [CrossRef]
  145. Manzari, N.; Matvienko-Sikar, K.; Baldoni, F.; O’Keeffe, G.W.; Khashan, A.S. Prenatal maternal stress and risk of neurodevelopmental disorders in the offspring: A systematic review and meta-analysis. Soc. Psychiatry Psychiatr. Epidemiol. 2019, 54, 1299–1309. [Google Scholar] [CrossRef]
  146. Simcock, G.; Laplante, D.P.; Elgbeili, G.; Kildea, S.; Cobham, V.; Stapleton, H.; King, S. Infant neurodevelopment is affected by prenatal maternal stress: The QF 2011 Queensland Flood Study. Infancy 2017, 22, 282–302. [Google Scholar] [CrossRef]
  147. Brouwers, E.P.; van Baar, A.L.; Pop, V.J. Maternal anxiety during pregnancy and subsequent infant development. Infant Behav. Dev. 2001, 24, 95–106. [Google Scholar] [CrossRef]
  148. Buitelaar, J.K.; Huizink, A.C.; Mulder, E.J.; De Medina, P.G.R.; Visser, G.H. Prenatal stress and cognitive development and temperament in infants. Neurobiol. Aging 2003, 24, S53–S60. [Google Scholar] [CrossRef]
  149. Laplante, D.P.; Hart, K.J.; O’Hara, M.W.; Brunet, A.; King, S. Prenatal maternal stress is associated with toddler cognitive functioning: The Iowa Flood Study. Early Hum. Dev. 2018, 116, 84–92. [Google Scholar] [CrossRef]
  150. Zhu, P.; Sun, M.S.; Hao, J.H.; Chen, Y.J.; Jiang, X.M.; Tao, R.X.; Huang, K.; Tao, F.B. Does prenatal maternal stress impair cognitive development and alter temperament characteristics in toddlers with healthy birth outcomes? Dev. Med. Child Neurol. 2014, 56, 283–289. [Google Scholar] [CrossRef]
  151. Keim, S.A.; Daniels, J.L.; Dole, N.; Herring, A.H.; Siega-Riz, A.M.; Scheidt, P.C. A prospective study of maternal anxiety, perceived stress, and depressive symptoms in relation to infant cognitive development. Early Hum. Dev. 2011, 87, 373–380. [Google Scholar] [CrossRef][Green Version]
  152. Li, J.; Robinson, M.; Malacova, E.; Jacoby, P.; Foster, J.; Van Eekelen, A. Maternal life stress events in pregnancy link to children’s school achievement at age 10 years. J. Pediatrics 2013, 162, 483–489. [Google Scholar] [CrossRef]
  153. Porter, E.; Lewis, A.J.; Watson, S.J.; Galbally, M. Perinatal maternal mental health and infant socio-emotional development: A growth curve analysis using the MPEWS cohort. Infant Behav. Dev. 2019, 57, 101336. [Google Scholar] [CrossRef]
  154. Van den Heuvel, M.; Johannes, M.; Henrichs, J.; Van den Bergh, B. Maternal mindfulness during pregnancy and infant socio-emotional development and temperament: The mediating role of maternal anxiety. Early Hum. Dev. 2015, 91, 103–108. [Google Scholar] [CrossRef]
  155. Nolvi, S.; Karlsson, L.; Bridgett, D.J.; Korja, R.; Huizink, A.C.; Kataja, E.-L.; Karlsson, H. Maternal prenatal stress and infant emotional reactivity six months postpartum. J. Affect. Disord. 2016, 199, 163–170. [Google Scholar] [CrossRef]
  156. Olulade, O.A.; Seydell-Greenwald, A.; Chambers, C.E.; Turkeltaub, P.E.; Dromerick, A.W.; Berl, M.M.; Gaillard, W.D.; Newport, E.L. The neural basis of language development: Changes in lateralization over age. Proc. Natl. Acad. Sci. USA 2020, 117, 23477–23483. [Google Scholar] [CrossRef] [PubMed]
  157. Laplante, D.P.; Brunet, A.; King, S. The effects of maternal stress and illness during pregnancy on infant temperament: Project Ice Storm. Pediatric Res. 2016, 79, 107–113. [Google Scholar] [CrossRef] [PubMed][Green Version]
  158. McMahon, C.; Boivin, J.; Gibson, F.; Hammarberg, K.; Wynter, K.; Saunders, D.; Fisher, J. Pregnancy-specific anxiety, ART conception and infant temperament at 4 months post-partum. Hum. Reprod. 2013, 28, 997–1005. [Google Scholar] [CrossRef] [PubMed][Green Version]
  159. Dubber, S.; Reck, C.; Müller, M.; Gawlik, S. Postpartum bonding: The role of perinatal depression, anxiety and maternal–Fetal bonding during pregnancy. Arch. Women’s Ment. Health 2015, 18, 187–195. [Google Scholar] [CrossRef] [PubMed]
  160. Otte, R.; Donkers, F.; Braeken, M.; Van den Bergh, B. Multimodal processing of emotional information in 9-month-old infants II: Prenatal exposure to maternal anxiety. Brain Cogn. 2015, 95, 107–117. [Google Scholar] [CrossRef]
  161. Mughal, M.K.; Giallo, R.; Arnold, P.; Benzies, K.; Kehler, H.; Bright, K.; Kingston, D. Trajectories of maternal stress and anxiety from pregnancy to three years and child development at 3 years of age: Findings from the All Our Families (AOF) pregnancy cohort. J. Affect. Disord. 2018, 234, 318–326. [Google Scholar] [CrossRef]
  162. Kikkert, H.K.; Middelburg, K.J.; Hadders-Algra, M. Maternal anxiety is related to infant neurological condition, paternal anxiety is not. Early Hum. Dev. 2010, 86, 171–177. [Google Scholar] [CrossRef]
  163. Cao, X.; Laplante, D.P.; Brunet, A.; Ciampi, A.; King, S. Prenatal maternal stress affects motor function in 5½-year-old children: Project Ice Storm. Dev. Psychobiol. 2014, 56, 117–125. [Google Scholar] [CrossRef]
  164. Grace, T.; Bulsara, M.; Robinson, M.; Hands, B. The impact of maternal gestational stress on motor development in late childhood and adolescence: A longitudinal study. Child Dev. 2016, 87, 211–220. [Google Scholar] [CrossRef][Green Version]
  165. Hansen, B.H.; Oerbeck, B.; Skirbekk, B.; Petrovski, B.É.; Kristensen, H. Neurodevelopmental disorders: Prevalence and comorbidity in children referred to mental health services. Nord. J. Psychiatry 2018, 72, 285–291. [Google Scholar] [CrossRef]
  166. Say, G.N.; Karabekiroğlu, K.; Babadağı, Z.; Yüce, M. Maternal stress and perinatal features in autism and attention deficit/hyperactivity disorder. Pediatrics Int. 2016, 58, 265–269. [Google Scholar] [CrossRef]
  167. Class, Q.A.; Abel, K.M.; Khashan, A.S.; Rickert, M.E.; Dalman, C.; Larsson, H.; Hultman, C.M.; Långström, N.; Lichtenstein, P.; D‘Onofrio, B.M. Offspring psychopathology following preconception, prenatal and postnatal maternal bereavement stress. Psychol. Med. 2014, 44, 71–84. [Google Scholar] [CrossRef][Green Version]
  168. Li, J.; Olsen, J.; Vestergaard, M.; Obel, C. Attention-deficit/hyperactivity disorder in the offspring following prenatal maternal bereavement: A nationwide follow-up study in Denmark. Eur. Child Adolesc. Psychiatry 2010, 19, 747–753. [Google Scholar] [CrossRef][Green Version]
  169. Walder, D.J.; Laplante, D.P.; Sousa-Pires, A.; Veru, F.; Brunet, A.; King, S. Prenatal maternal stress predicts autism traits in 6½ year-old children: Project Ice Storm. Psychiatry Res. 2014, 219, 353–360. [Google Scholar] [CrossRef]
  170. Zhu, P.; Hao, J.-H.; Tao, R.-X.; Huang, K.; Jiang, X.-M.; Zhu, Y.-D.; Tao, F.-B. Sex-specific and time-dependent effects of prenatal stress on the early behavioral symptoms of ADHD: A longitudinal study in China. Eur. Child Adolesc. Psychiatry 2015, 24, 1139–1147. [Google Scholar] [CrossRef]
  171. Varcin, K.J.; Alvares, G.A.; Uljarević, M.; Whitehouse, A.J. Prenatal maternal stress events and phenotypic outcomes in Autism Spectrum Disorder. Autism Res. 2017, 10, 1866–1877. [Google Scholar] [CrossRef]
Figure 1. Maternal distress transmission: placental and breastfeeding mechanisms.
Figure 1. Maternal distress transmission: placental and breastfeeding mechanisms.
Ijms 23 13932 g001
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Jeličić, L.; Veselinović, A.; Ćirović, M.; Jakovljević, V.; Raičević, S.; Subotić, M. Maternal Distress during Pregnancy and the Postpartum Period: Underlying Mechanisms and Child’s Developmental Outcomes—A Narrative Review. Int. J. Mol. Sci. 2022, 23, 13932.

AMA Style

Jeličić L, Veselinović A, Ćirović M, Jakovljević V, Raičević S, Subotić M. Maternal Distress during Pregnancy and the Postpartum Period: Underlying Mechanisms and Child’s Developmental Outcomes—A Narrative Review. International Journal of Molecular Sciences. 2022; 23(22):13932.

Chicago/Turabian Style

Jeličić, Ljiljana, Aleksandra Veselinović, Milica Ćirović, Vladimir Jakovljević, Saša Raičević, and Miško Subotić. 2022. "Maternal Distress during Pregnancy and the Postpartum Period: Underlying Mechanisms and Child’s Developmental Outcomes—A Narrative Review" International Journal of Molecular Sciences 23, no. 22: 13932.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop