The Impact of Maternal Stress on the Fetal Brain – A Summary of Key Mechanisms

MEDIATORS OF MATERNAL-FETAL STRESS

There are many ways that maternal stress has been hypothesized to affect fetal development during each of the critical phases of pregnancy. This review outlines the role of these mediators, how they are induced and the effect they can have on the offspring.

There are several mechanisms by which psychosocial stressors in the mother can affect the fetal brain. Elevated levels of cytokines can traverse the placental barrier and initiate a fetal immune response leading to neuroinflammation. Abnormalities in 5HT homeostasis may influence brain maturation. Elevated cortisol is broken down by the placental enzyme (11β-HSD-2) that inactivates 80-90% of maternal cortisol before it enters the fetus to protect the fetus from excessive maternal cortisol during acute phases of maternal stress. In heightened periods of stress this negative feedback mechanism may be disrupted leading to elevated cortisol and CRH levels that can disrupt fetal HPA axis regulation. Oxidative stress can impact brain development through the apoptotic and excitotoxic impact of ROS on neural tissue. Finally, stress changes vaginal microbiota which inturn can disrupt the developing gut-brain axis at an early stage resulting in neurobehavioural consequences in the child.

TRANS-PLACENTAL TRANSFER OF CORTISOL

Prenatal stress activates the HPA axis, with the adrenal cortex synthesizing and releasing cortisol. Cortisol is highly lipophilic and can pass the placental barrier to the fetus.

Research shows that the fetus actually relies on the mother for cortisol until the third trimester at which point it can then produce its own.

Although the fetus relies on maternal cortisol during gestation, there is a placental enzyme (11β-HSD-2) that inactivates 80-90% of maternal cortisol before it enters the fetus.

This is to protect the fetus from excessive maternal cortisol during acute phases of maternal stress.

Once inside the fetus, excess maternal cortisol can disrupt the fetal HPA axis by resetting the fetus’ negative feedback mechanism to its own cortisol production. This can result in permanent damage that can determine altered behavioral phenotypes in later life [4].

INDIRECT TRANSFER OF STRESS VIA CATECHOLAMINES

Psychological stress activates the sympathetic adrenal medullary system, which coordinates the release of norepinephrine (NE) and epinephrine (E) from the adrenal medulla.

These catecholamines are known to mediate short-term behavioral, metabolic and immunological responses to environmental stressors.

Catecholamines are hydrophilic and seemingly do not cross the placenta readily. However, excess catecholamines have been shown to impair fetal development possibly through indirect interactions.

Researchers suggest that NE and E can activate α-adrenergic receptors that vasoconstrict blood vessels in the uterus and placenta [5].

Psychological stress and subsequent increased vascular tone in the uterus and placenta reduces umbilical blood flow i.e  reduced utero-placental perfusion (UPP).

The effect of maternal catecholamines on UPP can retard growth in the fetus and even cause premature birth.

ROLE OF CYTOKINES AND THE MATERNAL IMMUNE RESPONSE

Psychosocial stress has been shown to be associated with an increased risk of prenatal infections. These infections can modify the immune system of the fetus via the maternal release of immune system modifiers known as cytokines.

Cytokines play an important role in stimulating or suppressing inflammation as well as also being closely linked to oxidative stress and reactive oxygen species (ROS).

Cytokines can pass through the placenta and enter fetal circulation where they can then directly interact with cells of the fetal immune system.

Although this cellular transfer of stress from the mother to the fetus is suggested to be a factor, much of the data in this field is conflicting and the biological mechanism is unclear.

There is however a possible role for stress-induced maternal inflammation whereby the up-regulation of pro-inflammatory placental genes results in changes in the developing fetal immune system.

This includes altered gene expression in the fetal hippocampus where there is an association with decreased learning potential, increased body weight and decreased insulin sensitivity in an offspring’s later life [6],[7]. We have covered the concept of neuroinflammation previously.

REACTIVE OXYGEN SPECIES (ROS) AND OXIDATIVE STRESS

Oxygen is necessary for life and is an important substrate in generating the energy-storage molecule ATP. During oxygen metabolism, between 0.2 to 2% of all oxygen molecules are reduced to ROS including the superoxide anion, the hydroxyl radical, and hydrogen peroxide.

An imbalance in the human body’s antioxidant defense mechanisms and the over-production of ROS is known as oxidative stress.

Food consumption, air pollutants, and medical drugs are all known to be exogenous factors that can cause an imbalance. However, psychological stress is also shown to increase oxidative stress markers [8].

ROS species have a relatively short half-life because they are so reactive and so are unlikely to transfer directly to the fetus.

Instead, a possible indirect interaction is between the maternal and fetus oxidative defense systems. This is whereby maternal stress induces fetal stress via a reduction in UPP response to cortisol [9].

Excessive ROS in most situations will induce severe cell damage by oxidation of lipids, proteins and DNA.

During pregnancy it is associated with preterm delivery, intrauterine growth restriction, and gestational diabetes, which all contribute to fetal programming that can affect the newborn in the long-term.

To understand more about neuroinflammation (the impact of inflammation and oxidative stress on the brain) check out these two videos; Neuroinflammation & Oxidative stress.

STRESS IMPAIRED MATERNAL MICROBIOTA

Gut microbiota and the gut-brain axis (GBA) is an integrated bidirectional communication pathway between the gut, its microbes and the brain.

Diverse microbial communities in the maternal host are essential in modifying the immune responses, CNS physiology and behavior as well as regulating the neuroendocrine system, including the HPA axis.

Psychosocial stress can cause disturbances in the maternal GBA as well as also disturbing other microbial communities in the human body such as the vaginal microbiota.

Here, psychosocial stress is hypothesized to increase the risk for bacterial and fungal vaginosis in women [10].

When the fetus passes through the birth channel there is a vertical transmission of vaginal microbiota and the colonization of the sterile fetal gut.

Psychosocial stress induced changes to the vaginal microbiota will affect what colonizes the fetal gut. One recent study in 2015 showed that there was an association between urovaginal infections during pregnancy and the development of autism spectrum disorder (ASD) [11].

NEUROPSYCHIATRIC IMPLICATIONS OF MATERNAL STRESS

Exposure to an adverse life event that causes psychosocial stress during pregnancy can affect mental health in later life [12]. This hypothesis implies that for some there is the possibility of the prenatal programming of mental illness and that a stressful in utero environment causes this.

Although epigenetic and genetic factors play a role in the heritability of neuropsychiatric disorders, the relationship and mechanisms that underpin it are likely to be multifactorial.

Prenatal Programming of Schizophrenia

Non-genetic and environmental risk factors include maternal viral infections, obstetric hypoxic complications and maternal stress [13]. Research into the prenatal programming of schizophrenia, however, has failed to find a plausible biological relationship to date [14].

The male fetal brain is more sensitive to prenatal stressors and neuroendocrine disturbances in the mother than female fetal brains.

A Danish registry study showed that the analysis of 1.38 million births revealed that exposure to the death of a relative during the first trimester of pregnancy significantly increased the risk of the male offspring developing schizophrenia [15].

Prenatal Programming of Autism Spectrum Disorders

In ASD, brain development is affected and symptoms do not occur until about 3 years of age. Inflammation in the mother may be implicated in the postnatal brain development and include inflammatory responses associated with diabetes, obesity, hypertension and microbial infections during pregnancy.

Research into the origins of ASD in children has suggested that a viral infection during the first trimester is associated with an increased risk of ASD [16].

In addition, during the third trimester, psychosocial stress is also associated with an increased risk of ASD developing in the offspring [17].

Prenatal Programming of Depression

Maternal depression during pregnancy has previously been reported to be associated with the development of depression in the offspring [18].

However, there are many inconsistent results and the impact, if any, of maternal stress and inflammation on programming of depression in the offspring is still unclear.

The mechanism of prenatal depression and the risk of the offspring developing depression may be through cortisol-induced changes to the HPA axis in the fetus [19].

Here, depression associated chronic stress during pregnancy could play a role in the development of behavioral and emotional problems in the fetus [20].

CONCLUSION

Maternal stress experienced during pregnancy can affect fetal programming that has ramifications on an individual’s risk to develop neuropsychiatric disease in later life.

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