Psychopharmacology and Pregnancy: Treatment Efficacy, Risks, and Guidelines 2014

5. Depression in Pregnancy and Child Development: Understanding the Mechanisms of Transmission

Andrew J. Lewis 

(1)

Faculty of Health, School of Psychology, Deakin University, Burwood, NSW, Australia

Andrew J. Lewis

Email: andrew.lewis@deakin.edu.au

5.1 Epidemiology of Perinatal Depression

5.2 Offspring Outcomes Following Maternal Depression

5.3 Mechanisms of Transmission

5.4 Prenatal Depression and Fetal Programming

5.5 The Role of Glucocorticoids

5.6 Development of the Fetal HPA System

5.7 Role of the Placenta

5.8 Epigenetic Regulation of Fetal Development

5.9 Conclusions

5.9.1 The Timing of Exposure to Depression

5.9.2 Specific or General Mechanisms

5.9.3 Treatment of Antenatal Depression as a Prevention Intervention

References

Abstract

The impact of depression in pregnancy and in the early postpartum period on neonatal and early child development has been well documented. Perinatal depression predicts poorer cognitive function, behavioural development, and emotional regulation in offspring. However, the mechanism through which this occurs requires clarification. This chapter provides a commentary on existing research, particularly that emerging from fetal programming, to consider possible mechanisms for this transmission of risk. This body of literature suggests that the timing of depression across the perinatal period is significant, and should be separated into exposures across each trimester of pregnancy and across the postnatal period with the timing and dose of depressive symptoms being clearly distinguished. Other cofounding exposures are both psychosocial in nature such as anxiety and stress and also teratogenic such as smoking, nutritional deficiencies, and medication exposures. Such confounds need to be carefully considered when interpreting the depression literature. Putative mechanisms through which prenatal depression impacts child development include direct genetic inheritance, shared adverse environments, elevated maternal stress response, alteration in vascular and placental function, and inflammatory pathways. Postnatal pathways have been more substantially investigated and probably involve maternal sensitivity, lower stimulation, and ongoing environmental stressors. The cumulative effect of both prenatal and postnatal factors should be a greater focus of research design in this field. Prevention and intervention models to reduce the deleterious effects of maternal depression in the preconception, antenatal, and postnatal period can be informed by further research on these mechanisms of transmission.

Keywords

PreventionMaternal mental healthPerinatal depressionFetal programmingEpigeneticsDevelopmental origins of health and disease (DOHaD)

Optimising child developmental outcomes requires a life-course model able to consider the complex unfolding of developmental processes that commence prior to the child’s conception. The key developmental transitions are those leading up to conception, from pregnancy to birth, the period of lactation and early infancy, childhood, and then the pubertal transitions into the reproductive years of adult life. Conceptualising each transition provides a bio-developmental framework upon which all interventions, be they pharmacological, psychosocial, or lifestyle based, can be properly conceived, developed, and evaluated (Shonkoff 2010). Although it goes without saying that optimal early child development builds upon optimal fetal development, too much developmental research has considered birth to be a starting point to investigate development and too much psychiatric research has failed to consider the reproductive and child developmental consequences of adult psychiatric disorders.

At birth a neonate in a state of good health is able to thrive over the neonatal period by eliciting and receiving the benefit of high-quality parental investment. However, earlier developmental setbacks such as reduced gestation, low birth weight, deleterious pregnancy exposures, or complications during pregnancy or birth can negatively impact on the health and mental health of an individual across the life course. It follows that a child’s development across such transitions cannot be considered apart from the mother’s health, mental health, and well-being. An infant is more likely to experience optimal development in a context of good maternal health and mental health commencing in the preconception period and extending across her pregnancy.

Maternal mental health during pregnancy is not only a major psychosocial stressor, but increasingly understood to also be a major physiological stressor. The most prevalent issues are depression, anxiety, and stress exposure. Alongside obesity, nutrition, and metabolic disorders, compromised maternal mental health is increasingly recognised as one of the major complications of pregnancy. Efforts to optimise child development require researchers, clinicians, and policymakers to address such complications through interventions delivered at preconception, pregnancy, and postnatally. The high population prevalence of mood and anxiety disorders over pregnancy is of considerable public health concern given the impact on mothers themselves, their offspring, and child’s experience of postnatal care. This chapter will focus on perinatal depression and, following a brief review of the findings on child and maternal outcomes, will consider in detail the putative biological mechanisms by which perinatal depression translates into poor outcomes for offspring.

5.1 Epidemiology of Perinatal Depression

Perinatal Depression is one of the most common complications of pregnancy affecting 7–13 % of pregnant women and 10–15 % of women in the 6 months following their child’s birth (Bennett et al. 2009). There is a wide range of severity in depressive symptoms ranging from the so-called maternity blues, which is very common and typically transitory, through to postpartum psychosis which has a prevalence of less than 1 %. Depressive symptoms meet diagnostic criteria and require clinical intervention once they are characterised by persistently dysphoric mood and anhedonia as well as additional symptoms which can include sleep and appetite disturbance, fatigue, irritability, lack of concentration, and in some cases suicidal ideation and attempts. It is not uncommon that depressive disorders are also accompanied by feelings of lowered self-worth, hopelessness, social withdrawal, and an inability to cope. These symptoms are related to neurobiological changes that have mostly been investigated in terms of monoaminergic and glutamatergic systems or as dysregulations of the hypothalamic–pituitary–adrenal (HPA) axis and its interface with hippocampal activation. This neuroendocrine system involves corticotropin-releasing hormone (CRH), glucocorticoids, and brain-derived neurotrophic factor (BDNF). Clearly, other neural regions are involved and research has examined the nucleus accumbens and amygdala as brain regions involved in the regulation of motivation, eating, sleeping, energy level, circadian rhythm, and reward systems which are all known to be dysregulated in depression (Nestler et al. 2002). This complex group of depressive symptoms occurring within the context of the profound biological and psychosocial changes that accompany pregnancy suggests that our use of the term ‘perinatal depression’ is shorthand for a complex and highly disabling condition.

The prevalence of perinatal depression has also been well established: both antenatally and postnatally. Gaynes and colleagues systematically reviewed 28 papers reporting prevalence of perinatal depression and found that the combined point prevalence estimates ranged from 6.5 % to 12.9 %. Over the perinatal period from pregnancy up to 3 months postpartum the cumulative prevalence reached 19.2 % of women diagnosed with a major depressive episode with the majority occurring after delivery (Gaynes et al. 2005). Other studies have shown that the duration of the perinatal depressive episode is related to two key factors: the severity of symptoms and access to treatment (Dennis 2005). Antenatal mood disorders are also highly prevalent with a systematic review by Bennett reporting prevalence rates of depressive disorders in pregnancy as 7.4 %, 12.8 %, and 12.0 % across each trimester (Bennett et al. 2004). Leigh and Milgrom reported Australian data from the Beyondblue National Postnatal Depression Program showing a prevalence rate for depression at 28–32 weeks of pregnancy at 16.9 % and at 10–12 weeks postnatally at 11.2 % (Leigh and Milgrom 2008).

It is particularly important given this paper’s focus on mechanisms to note that the continuity between antenatal depression and postnatal depression is high. Around 50 % of women with postnatal depressive symptoms have also experienced depression during their pregnancy (Gotlib et al. 1989). Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) Heron reported that the majority of cases of postnatal depression and anxiety were preceded by antenatal depression and anxiety, respectively (Heron et al. 2004). This study found that women presenting with antenatal anxiety were more than three times more likely to present with postnatal depression at 8 weeks and 8 months. Leigh and Milgrom used a multivariate regression model which included a large number of demographic and historical factors, antenatal depression, anxiety and stressors, as well as personality variables to show that, in the final model, antenatal depression (β = 0.47), parenting stress (β = 0.32), and history of depression (β = 0.15) were the only significant predictors of postnatal depression after controlling for these other variables. The final regression model explained an impressive 66 % of the variance in postnatal depressive symptoms (Leigh and Milgrom 2008).

5.2 Offspring Outcomes Following Maternal Depression

Child outcomes following perinatal depression have been investigated in many studies. A significant body of research investigating perinatal depression has now examined outcomes including birth outcomes, child and adolescent mental and behavioural disorders, cognitive development including language development and attention capacity, and socio-emotional development in terms of temperament and attachment. These studies have been well reviewed in several recent papers (Schlotz and Phillips 2009; Talge et al. 2007; Swanson and Wadhwa 2008).

In short, for prenatal exposure, maternal prenatal stress in various forms has been found to be associated with a number of mental health disorders. Some of this previous research has been based on ecological exposures such as disaster records or retrospective assessment of prenatal stress. Khashan et al. (2008) used two Danish national registries and found that maternal prenatal exposure to a family bereavement during the first trimester was related to an increased risk of schizophrenia. Similar studies have found associations between high pregnancy stress and risk of psychosis (Spauwen et al. 2004), storm or hurricane exposure and autism (Kinney et al. 2008), and earthquake exposure predicting depressive symptoms in offspring (Watson et al. 1999). A number of large prospective cohort studies have more convincingly measured maternal anxiety and depressive symptoms experienced in pregnancy and also show that these predict child mental health outcomes. Loomans et al. (2011) found that maternal state anxiety measured at 16 weeks gestation was significantly associated with an increased likelihood of inattention/hyperactivity problems for boys but not for girls. O’Connor et al. (20022003) reported that prenatal maternal anxiety measured at 32 weeks predicted inattention/hyperactivity symptoms also in boys at 4 and 6.5 years. Clavarino et al. (2010) also found that high prenatal maternal anxiety was associated with attention problems at 5, but that these remitted by 14 years, while anxiety problems persisted from 5 to 14 years. Robinson et al. (2008) found that major life stressors were associated with small increases in behavioural problems at ages 2 and 5 and emotional problems at age 5. These are a small selection of the studies with larger samples, which consistently show an impact of maternal mental health in pregnancy on child behavioural, attention, and emotional outcomes.

In terms of postnatal depression, infants of depressed mothers show more negative affect and lower sensitivity (Dawson et al. 1992) and offspring may experience inadequate physical and verbal stimulation (Field 1998). These effects of postnatal depression have been shown to extend to adolescents who continue to display increased waking cortisol levels (Murray et al. 2010). It is well established that postnatal depression reduces the sensitivity of mother when interacting with the child and this results in poorer stress regulation and insecure attachments. A meta-analysis of seven studies found that the infants of depressed mothers were less likely to have a secure attachment and more likely to display avoidant and disorganised attachment (Martins and Gaffan 2000). Essentially, the putative mechanism here is the negative effects of postnatal maternal caregiving in the context of maternal depression.

The literature on temperament outcomes for infants and in early childhood is particularly interesting since it suggests important mechanistic pathways to what has previously been considered a highly genetically heritable trait of emotional regulation. Field reports in her systematic review that raised cortisol levels in pregnancy have been associated with increased fussiness and negative behaviour in previous studies and maternal reports of infant negative reactivity (Field 2011; Davis et al. 2007). Recent studies have found that maternal life stressors over pregnancy predict infant cortisol levels, reactive temperament (Lewis and Olsson 2011), and higher resting cortisol throughout the day in adolescence (Van Den Bergh et al. 2008).

There are important caveats to consider when interpreting this literature. Our own study of antidepressant use in Australia using the population Longitudinal Study of Australian Children (LSAC) showed that not only was antidepressant use associated with higher levels of depression, but was also associated with higher rates of multiple exposures such as smoking, other medication use, and health difficulties (Lewis et al. 2012). There is also high comorbidity between maternal obesity and mental health symptoms in pregnancy.

5.3 Mechanisms of Transmission

Broadly, there are three potential mechanisms whereby maternal perinatal depression could be transmitted to negative offspring outcomes. In summary, these are a model based purely on genetic heritability, secondly, the influence of shared environmental factors which contribute equally to maternal perinatal depression and impact on child development, and thirdly, there is the idea that maternal depression, in a variety of possible mechanisms, programmes fetal and early infant development in a manner which leads to poor outcomes for the child.

In terms of a genetic model, it is widely accepted that genetic factors play an important part in the risk for depression. Epidemiologic studies using behavioural genetic approaches generally suggest that 30–40 % of the risk for depression is heritable (Sullivan et al. 2000). However, the isolation of which specific mechanisms of heritability are responsible encounters several issues. The first is the pervasive ‘missing heritability’ problem which plagues studies of association that are based on candidate genes which typically account for a small fraction of the heritability estimates (Manolio et al. 2009). One example which has been prominent in the literature is a repeat length polymorphism in the serotonin transporter promoter region (SLC6A4) which codes for a protein that transports synaptic serotonin and is the target of SSRIs. However, the effect of this genetic variant is small and tends to be stronger for depression-associated personality or behavioural traits such as neuroticism or suicidality (Costas et al. 2010). Polymorphisms in MAOA and COMT have also been found to be associated with perinatal depression onset in the context of stressful events (Doornbos et al. 2009). Using data from the Cardiovascular Risk in Young Finns birth cohort followed since 1980 Jokela examined the serotonin receptor 2A gene and found that a polymorphism appears to moderate the relationship between mother’s self-reported maternal nurturance of the child and the development of depressive symptoms in adulthood (Jokela et al. 2007). Perhaps a more profound limitation in the genetic heritability model concerns the rapidly shifting concept of heritability itself, which is moving beyond gene-based models in the light of germ line heritability conferred with epigenetic heritability (Lewis 2012).

While such findings are suggestive, there remains difficulty isolating specific candidate genes for depression that is probably due to there being many genes involved which produce such a complex phenotype, each gene only contributing a small effect. It is also important to recognise that a purely genetic model is itself biologically implausible given that genes operate within a complex biological system which provides the context of their biological action (Meaney 2010). There may also be a number of different genetic pathways that confer risk and there are complex interactions over time between genes, epigenetic effects, and environmental factors.

Recent evidence concerning common genetic variants for a range of mental health disorders adds an intriguing possibility that across disorders such as schizophrenia, depression, and bipolar disorder common genetic variants confer a genetic risk disposition which becomes shaped into different disorders by subsequent developmental, environmental, or stochastic factors. A recent meta-analysis examined whether variants in methylenetetrahydrofolate reductase (MTHFR), a gene involved in processing folic acid, contribute to shared genetic vulnerability to a combined group of psychiatric disorders (schizophrenia, bipolar disorder, and unipolar depressive disorder) and found a 26 % increased association with one polymorphism (Peerbooms et al. 2011).

Here we have said nothing of the possible genetic links between perinatal depression and non-mental health outcomes in children such as cognitive and psychosocial outcomes via pleiotropic genetic effects. The genetic model can also apply to offspring genetically inheriting certain sensitivities or predispositions to behave in a certain manner, which exposes individuals to certain environments which may be adverse (Kendler et al. 1995). This is referred to as gene–environment correlation.

A second model of transmission which should be briefly mentioned is the circumstance in which the environmental conditions, which contribute to prenatal and postnatal depression, also make a contribution to adverse child outcomes. In this case a direct association between perinatal depression and child outcome is actually confounded by a third variable contributing to both. Relevant factors here include low socio-economic status and other perpetuating adversities which create stress, limit opportunities, and possibly contribute to lack of support for new parents. Socio-economic status may imply differences in access to material and social resources for children and their parents (Bradley and Corwyn 2002). Socio-economic status is one of the most widely investigated social determinants of child developmental outcomes and will not be further reviewed here.

There is also clearly a major role for postnatal transmission of maternal mood on offspring outcome. The fetal stress response is rapidly transformed postnatally into a circadian rhythm with a peak around the time of waking which starts to operate within a few months of birth for a term baby (Price et al. 1983). The normal circadian rhythm can facilitate termination of the HPA stress response and conversely disturbances in the daily rhythm may contribute to HPA stress dysregulation (Gunnar and Quevedo 2007). This interaction postnatally between circadian rhythm, stress response and sleep patterns illustrates the hierarchical nature of development where basic bio-behavioural structures established in fetal development can also come to function as the platform for more complex developmental systems. Although these have not been so clearly articulated, similar patterns may exist for the development of interpersonal, emotional, and behavioural responses further into childhood and adolescence (Gluckman and Hanson 2006). Much more could be said on postnatal mechanisms, but the focus in this chapter is on the prenatal period.

5.4 Prenatal Depression and Fetal Programming

The main focus in this chapter is to consider emerging research on the manner in which maternal depression disrupts development through prenatal programming of later development. Animal models of such transmission have been well developed, typically based on inducing either pharmacological or environmental stresses at various times across the perinatal period in rodent models and non-human primates (Darnaudéry and Maccari 2008). Such models have established that the timing of the stress, its intensity and duration, and the gender of the offspring are critical factors influencing offspring outcomes (Field 2011). Such studies also demonstrate neurodevelopmental alterations occurring in the hippocampus, prefrontal cortex, the amygdala, and the nucleus accumbens following maternal stress. The offspring of stress exposed dams go on to display anxious and depressive behaviours (or at least animal analogues of such disorders), but interestingly memory impairments have also been documented (Darnaudéry and Maccari 2008). Such maternal stressors are thought to be transmitted via increases in maternal corticosteroid levels also being transmitted to the fetal brain and thus influencing the development of the offspring HPA system. This programmes later emotional and behavioural disturbances in the offspring such as fearfulness, impulsivity, and substance use, which often become more pronounced when the animal is subjected to a later stressor.

Weinstock has shown in animal studies that offspring outcomes are sex specific which may be due to higher cortisol exposure in males decreasing fetal testosterone, but in females this alters catecholamine activity (Weinstock 20072011). Weinstock suggests that learning deficits are more readily seen in prenatally stressed males while females show anxiety, depression, and an increased response of the HPA axis to stress—findings which are similar to human population studies showing higher vulnerability to attention problems in males and possible links to the well-established rise of depression and anxiety in female adolescents.

There is also a substantial literature on the reversibility of the effects of maternal stress in animal models which cannot be reviewed here. Suffice to say that environmental enrichment and anti-depression treatments appear to ameliorate maternal stress exposures in these animal models. While these models are critical to understanding biological mechanisms and to testing possible interventions, their interpretation needs to be approached with caution. It should be noted that the species-specific ontogeny of the HPA system is important to consider when applying such findings to humans since exposures at different points in fetal and postnatal development may influence various systems involved in neuroendocrine and autonomic responses to stressors and the specific timing and degree of fetal HPA development varies considerably across mammalian species. So too it is difficult to model depression exposure in an animal model given the mood and cognitive components.

5.5 The Role of Glucocorticoids

There has been considerable focus on the early development of the hypothalamic–pituitary–adrenal (HPA) system which is also linked to maturation of other systems responsible for the regulation of circadian rhythms, physical growth, and the integration of limbic-cortical processes. The HPA system plays a critical part in early development, not only in stress regulation, but also in sleep, feeding, emotions, and emotion regulation (Lupien et al. 2009).

Glucocorticoids are responsible for regulation of metabolic functions and the regulation of stress. In normal development glucocorticoids have widespread programming and developmental functions for the fetus across a wide range of tissues such as lung, liver, thymus, and brain and this continues in postnatal development. There are major changes in glucocorticoid function over pregnancy. In the course of a normal pregnancy maternal cortisol increases, reaching a peak during the third trimester, suggesting a gradual upregulation of the maternal HPA axis across pregnancy (Jung et al. 2011). One source is the placenta, another is that maternal adrenal glands show greater sensitivity during pregnancy (Lindsay and Nieman 2005), and another is that increasing oestrogen levels over pregnancy reduce the breakdown of cortisol (Field 2011).

Several lines of evidence suggest that perinatal exposure to maternal depression is associated with deregulation of the child’s HPA response to stress, increasing the risk for future stress-related disorders. Higher levels of corticotropin-releasing hormone (CRH) in pregnancy have been associated with higher rates of depression (Rich-Edwards et al. 2008). There is some evidence that higher CRH is transmitted to the offspring. Azak reported that infants of mothers with depression and anxiety had high cortisol production from morning to bedtime and higher bedtime values and the effect was more enduring in children who had mothers with depression (Azak et al. 2013). Naturally this raises the question of whether the child outcomes referred to above, such as emotional and behavioural problems, are a direct effect of fetal programming or are an effect mediated by the offspring’s early socio-emotional experiences in the context of a dysregulated stress response.

There are also intriguing effects of patterns of neurotransmitter function which appear to be transmitted from mother to offspring. Over a series of papers Field reported across several monoamines that neonates of depressed women had biochemical profiles that mimicked their mothers’ antenatal profiles. She identified similar patterns for elevations in noradrenaline and lowered levels of dopamine and serotonin (Field 2011). The relationship between changes in glucocorticoid function and monoamine regulation for antenatally depressed mothers remains a compelling question. So too does the functional significance of these changes for early neural development in the fetus and in early childhood social and emotional development.

5.6 Development of the Fetal HPA System

Recent evidence suggests that exposure of the fetus to high maternal levels of glucocorticoids has long-term effects on child neurodevelopment. In a study of intrauterine exposure to synthetic glucocorticoids, Davis et al. showed an impact on development of the anterior cingulate cortex, which was associated with affective symptoms in children 6–10 years of age (Davis et al. 2013). In another study it was found that offspring of postnatally depressed mothers display larger amygdala volumes and have higher cortisol levels which leads to higher levels of internalising problems (Bagner et al. 2010).

The development of the HPA axis in the human fetus is a complex process involving maturation of fetal organs as well as interaction with placental and maternal endocrine systems (Bolt et al. 2002). In late pregnancy, a rise in fetal cortisol levels is necessary to stimulate the development of organ systems such as the lungs. However, as Meaney has discussed, this necessary aspect of fetal development shows that glucocorticoids function differently in distinct fetal tissue. Across most mammals increased neural exposure to glucocorticoids reduces neurogenesis and synaptic plasticity, suggesting that tissue-specific transcription factors may regulate glucocorticoid receptors, allowing protection for fetal neural development (Meaney 2010). It is also clear that an excess of fetal glucocorticoids may result in growth restriction of the fetus as well as influencing the postnatal adaptation and activity of the pancreas, pituitary–adrenal axis, and cardiovascular activity (Challis et al. 2001).

Postnatally an adaptive stress response occurs via perceptual cues relating to threat, disruption of expectancies, physical pain, infection, or metabolic crisis. Such cues are communicated to the hypothalamus via specific pathways. These signals are integrated in the hypothalamic paraventricular nucleus (PVN) where neurons expressing corticotropin-releasing hormone (CRH), in collaboration with other peptides such as vasopressin (AVP), stimulate the release of corticotropin hormone (ACTH) from the anterior pituitary (De Kloet et al. 2005). When released into circulation from the pituitary ACTH stimulates the adrenal cortices to synthesise and release cortisol. In fetal development the link between pituitary ACTH and adrenal cortisol appears to be established some time after week 20 of gestation (Bolt et al. 2002).

In early gestation, the fetal adrenal cortex produces small amounts of cortisol which gradually increases during the third trimester (Bolt et al. 2002). Across the second trimester placental ACTH, in combination with other placental hormones, regulates fetal production of adrenal steroids. By the third trimester the fetal pituitary gland seems to become integrated with the fetal adrenal cortex (Bolt et al. 2002). By late gestation the human fetal HPA axis is well developed and functions as a stress response system in response to stressors such as hypoxia or nutrient restriction. Therefore, external factors that reduce uterine vascular flow may initiate a fetal stress response similar to that experienced postnatally (Phillips and Jones 2006). Over the third trimester HPA activation begins to function according to its well-known negative feedback mechanism whereby mineralocorticoid and glucocorticoid receptors that are expressed extensively across the hypothalamus and hippocampus operate to inhibit the stress response (De Kloet et al. 2005). However, these two receptors play different roles in modulating both the stress response and the circadian rhythm. [Detailed reviews of HPA system and its fetal development are available in De Kloet et al. (2005)].

5.7 Role of the Placenta

There is a growing interest in the placenta as a critical agent in the transmission of maternal depression and infant outcomes. Placentation is a process which commences with blastocysts attaching to the uterine endometrium. The functioning placenta comes to serve a complex array of functions for the fetus including those of the lungs, intestine, kidney, liver, and a wide range of endocrine functions analogous to the pituitary and gonads (Luckett 1976). The investigation of placental biology in women who are depressed antenatally holds considerable promise in terms of understanding the biological mechanism involved in transmission of risk to offspring (Kaplan et al. 2008). The placenta functions as a temporary endocrine structure which regulates the transfer of nutrients to the fetus, but also protects the fetus from the growth-inhibiting effects of maternal glucocorticoids (Cottrell and Seckl 2009).

The placenta serves as a critical interface between maternal and fetal physiology and, in this respect, regulates the transfer of glucose, amino acids, ketones, and fatty acids. Alterations in maternal hormone levels across pregnancy potentially alter fetal development and conversely the production of placental hormones influences maternal physiology (Haig 1993). This implies a conceptual model where, across gestation, the maternal–fetal dyad is mostly mediated via the placenta which operates in a transactional manner across these two distinct organisms to facilitate fetal development. While it is clear that a proportion of such development is directed in a species typical manner by genomic information, there is also a significant role for input from the intrauterine environment which shapes the trajectory of early development.

There is an increasing research focus on the role of the placenta in the mediation of maternal prenatal distress and its impact on fetal development. Much of this research has focused on the enzyme type 2 isoform of 11beta-hydroxysteroid dehydrogenase (11β-HSD2) which specifically inactivates glucocorticoids, is highly expressed within the placenta, and has been suggested to play a role in the ontogeny of the fetal HPA axis (Cottrell and Seckl 2009). The expression level of 11β-HSD2 in the placenta directly influences the exposure of the fetus to circulating maternal stress hormones that cross the fetomaternal interface. Circulating cortisol concentrations in the fetus are typically around 13-fold lower than those in the mother, but there are portions of the placenta with less 11β-HSD2 enzyme allowing the fetus to be exposed to maternal cortisol in proportion to maternal cortisol level over pregnancy (O’donnell et al. 2009). In most cases placental 11β-HSD2 substantially reduces maternal cortisol transfer; however, around 10–20 % of maternal cortisol still contributes to fetal cortisol (Challis et al. 2001). Furthermore, the source of individual variation in placental 11β-HSD2 function remains an area of intense research focus at the present time with maternal stress, diet, and infection during pregnancy under current investigation.

Placental 11β-HSD2 represents a key biomarker of fetal stress biology and one of the earliest indicators that a child is on a pathway of high stress reactivity. Two recent studies have direct relevance. O’Donnell reported a 30 % reduction in placental 11β-HSD2 expression when mothers experienced prenatal anxiety and depression (O’Donnell et al. 2012). A recent paper failed to replicate O'Donnell's findings and also reported no effect of SSRI treatment on levels of placental 11β-HSD2 gene expression (Ponder et al. 2011).

While the placental passage of cortisol is clearly an important mechanism for transmission of the effects of antenatal depression, this supposes that the effect is a direct one. Fetal brain development would need to be directly impacted by increased cortisol exposure. While this is plausible, there is an alternative hypothesis which is that conditions which impose high stress on a pregnant woman such as depression and anxiety have an impact on fetal development via restriction of intrauterine Arterial blood flow which induces hypoxia and limits nutrient supply to the developing fetus. Raised levels of maternal noradrenaline are associated with intrauterine arterial resistance and this mechanism requires additional investigation (Field 2011; Teixeira et al. 1999).

Another possible mechanism to mention is the role of immune function. While one of the adaptive responses to acute stress is to mobilise the immune system, chronic stress and the chronic production of stress-related hormones suppress immune function. At the same time cytokine responses to inflammation are known to activate the HPA axis. A number of studies show that maternal exposure to infection increases the release of pro-inflammatory cytokines into the circulation (Weinstock 2005). Excess levels of these cytokines could induce premature birth and may be linked to the development of asthma and allergies. Again, it remains unclear whether cytokine exposure directly influences fetal neural development, or creates fetal distress via arterial resistance, or the impact on child development occurs via growth restriction and reduced gestational length. Here the timing and type of infection are significant factors. For example, during embryogenesis, the developing embryo is highly sensitive to infections such as rubella which have a direct effect on the development of organs. When maternal circulation is established via the placenta, the rate of fetal growth and development can be influenced by malaria infection (Gluckman et al. 2007).

5.8 Epigenetic Regulation of Fetal Development

Another intriguing aspect of early biological mechanisms is the intrauterine programming by maternal depression of gene expression in the developing fetus. ‘Epigenetics’ describes the study of all heritable changes in gene expression that are not encoded by the DNA sequence itself (Schroeder et al. 2011). Epigenetic programming of fetal and infant development may be induced by environmental signals transmitted via the mother during prenatal and postnatal development, but it is also increasingly clear that genetic factors also play a role directly programming fetal development and also influencing epigenetic processes. Epigenetics involves changes in the many chromatin functions which regulate tissue- and cell-specific gene expression. These include methylation of CpG sites across the genome, that is, a sequence within DNA where a cytosine nucleotide occurs before a guanine and can be linked by phosphate. The addition of a methyl group to cytosine within the DNA sequence, or more likely multiple methylation of CpG islands leading up to promoter regions, can silence the expression of a particular gene and this effect can be particular to a given cell line or tissue. Another epigenetic mechanism which is increasingly a focus is modification of histone sites which produces the opposite effect of making DNA available for transcription.

In previous studies, prenatal maternal stress and depression have been shown to alter epigenetic programming of genes found in placental tissue and cord blood. Although these tissues are peripheral to fetal brain development, their methylation status may well be an important biomarker for neural development. A number of studies are now providing such evidence of alterations in epigenetic programming as an effect of maternal mental health within specific genes associated with fetal neurodevelopment. For example, one strategy has been the use of high-throughput sequencing techniques to examine genome-wide DNA methylation across initially 27,000 CpG sites, in order to examine the effect of exposure to psychotropic medications and psychiatric illness on the methylation of genes within both placental tissue and umbilical cord blood (Schroeder et al. 2012; Smith et al. 2012). In one such study, numerous sites where the CpG methylation is different between those fetuses exposed to an antiepileptic compared to those who were not exposed have been identified. However, high-throughput sequencing technology is developing rapidly with considerable increases in genomic coverage now available. There is considerable interest in how to best analyse and interpret data on such a massive scale so it is likely such results are preliminary.

Another epigenetic approach is to select genes of known interest to fetal neurodevelopment, so-called candidate genes, and to examine the effect of maternal depression on epigenetic markers and, in some cases, gene expression within tissues of interest. The glucocorticoid receptor gene NR3C1 is one of the most well-characterised and investigated HPA axis-related genes. Oberlander and colleagues found elevated methylation of NR3C1 in cord blood samples from infants born to mothers with depression during the third trimester of pregnancy (Oberlander et al. 2008). In this study, infant HPA reactivity was assessed at 3 months of age using a habituation information processing task and levels of NR3C1 DNA methylation in fetal cord blood predicted infant cortisol response to stress. In a recent study, Radtke and colleagues examined the methylation status of NR3C1 in mothers and their children 10–19 years after birth and remarkably found that in the children methylation status of this gene was associated with their mother’s experience of partner violence during pregnancy (Radtke et al. 2011), suggesting that epigenetic processes operating in pregnancy may well have long-term developmental consequences.

The major challenge for epigenetic research seeking to examine the impact of maternal depression is to establish the functional significance and casual pathway for genomic regions where differences in epigenetic profile can be established for specific fetal exposures. For offspring outcomes such as cognition, emotional development, growth, and behavioural development, peripheral tissues can be readily collected such as cord blood, buccal cells, or placental tissue, but establishing their role as biomarkers of relevant outcomes requires carefully controlled studies and replication of associations of these epigenetic markers with later child outcomes. Findings of this kind are beginning to emerge, but this highly promising area is in its infancy.

5.9 Conclusions

5.9.1 The Timing of Exposure to Depression

It is significant that the global definition of perinatal depression includes both prenatal and postnatal maternal depression and therefore does not allow us to differentiate between the effects derived from intrauterine vs. postnatal effects. The strong continuity between antenatal and postnatal depression needs to be considered in all study designs of child outcomes. Studies commencing data collection only in the postpartum period are missing important pregnancy factors. Careful consideration of the relative impact of exposure to maternal depression during fetal development and during early childhood is required to understand child developmental outcomes. Exposures in the antenatal and postnatal period may cause different effects and, in many cases, the effect of exposure across both periods may be cumulative or interactive.

The bulk of the evidence, and current practice in perinatal mental health, is concerned with addressing postnatal depression and anxiety so as to improve the chances of more effective parenting postnatally. However, findings emerging from fetal programming research suggest that child stress biology is probably being established during the intrauterine period and that interventions ought to be focused equally on preconception and pregnancy mental health and stress exposure of mothers.

5.9.2 Specific or General Mechanisms

At present it remains unclear whether the mechanism through which depression in pregnancy is transmitted to the child is a general effect of maternal adversity, or may confer highly specific risks to the child's development. The problem is compounded in studies of fetal exposure which consider such exposures in simplistic terms. A good example is the frequently evoked Dutch famine offspring outcomes which are often used as a paradigm of nutritional insufficiency. However, the circumstances of military siege are surely high stress exposures, not to mention the rate of depression and anxiety for these mothers which are unknown. Since antenatal depression is associated with lower birth weight and preterm delivery it is not surprising that associations have also been found with later metabolic disorders such as hypertension and insulin resistance.

While this issue remains elusive, translation of these findings into interventions will also be impeded. At this point the risk factors for child development are well known. However, both exposures and outcomes need to be specific and measureable to enable characterization of biological mechanisms (Waterland and Michels 2007).

5.9.3 Treatment of Antenatal Depression as a Prevention Intervention

Once we understand clearly the effect of each exposure in terms of its discrete mechanisms and probably mechanisms, opportunities will arise for very well-targeted interventions. These may be pharmacological, psychosocial, or lifestyle-based interventions.

There can be little doubt however that higher level functions of cognitive development and skill acquisition depend on, and build on, the more basic functions of emotional regulation and adaptation in the face of challenge. As James Heckman has repeatedly pointed out, investment in interventions targeted at this foundation of human development brings the greatest reward on investment (Knudsen et al. 2006).

While the specific mechanisms for the transmission of antenatal depression require further research, the epidemiological evidence for a clear association between antenatal and postnatal depression and poorer child outcomes is very clear. The evidence is compelling that antenatal depression ought to be a key target in prevention efforts aimed at improving mothers’ mental health in the first instance, and with major flow on effects for improvement in maternal health and child development. It is difficult to underestimate the significance of these efforts for ensuring the optimal start to life.

Increasingly economic modelling of interventions targeting early development makes a compelling case that this is the ideal period in which to prevent not only mental health disorders but possibly a range of other metabolic and cardiovascular disorders.

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