Article summary with Premature birth and developmental programming: Mechanisms of resilience and vulnerability by Lammertink a.o. - 2021

What can be sources of stress after premature birth?

Stressors are defined as any real or interpreted threat to the physiological or psychological integrity of an individual that results in physiological and/or behavioral responses. Postnatal stressors can be divided into physical, environmental, and maternal stimuli or events:

• With regards to physical stress, preterm infants have an hypersensitivity to pain as their pain transmission and modulation are still underdeveloped. Two main categories of pain-related stressors are identified: acute procedural stress is triggered by a specific noxious stimulus, whereas acute prolonged stress represents a longer time duration with a distinguishable beginning and expected endpoint.
• With regards to environmental postnatal stress, continuous loud noise has adverse physiological effects on preterm infants and induces stress behaviors. Excess auditory stimulations are associated with decreased oxygen saturation, increased heart rate and blood pressure, and alterations in sleep-wake state.
• With regards to maternal care, physical and emotional closeness may become obstructed and increase feelings of separation and negatively impact mother-infant attachment. Preterm infants may be less responsive to parental cues and show more negative expressions, also affecting mother-infant attachment. Finally, mothers of preterm infants spend less time holding, talking to, and looking at their infant.

What is the role of the developing autonomic nervous system in fetal stress response?

The most immediate response to a stressor is modulated by the autonomic nervous system by maintaining physiological homeostasis. During the third trimester, the fetal autonomic nervous system is changing rapidly. It is possible that exposure to stressors during that period affects the development of the autonomic nervous system and function.

What is the role of the hypothalamic-pituitary-adrenal axis in fetal stress response?

The hypothalamic-pituitary-adrenal axis (HPA-axis) secretes glucocorticoids which acts on several organ systems to mobilize energy reserves. In a fetus, the HPA-axis is still developing and maturing. Preterm-born infants are neuroendocrinologically immature and their stay at intensive care associated with stressful events may disturb the central regulation of the HPA-axis. Prematurity may be characterized by the inability to maintain homeostasis while enduring acute stress.

Which neural networks are implicated in the fetal stress response?

Three neural networks are identified, namely:

• Default mode network (posterior cingulate cortex, hippocampus, parahippocampal cortex).
• Salience network (dorsal anterior cingulate cortex, frontoinsular cortex, amygdala). During stress, this network is upregulated, facilitating increased vigilance and attentional reorienting, and autonomic-neuroendocrine control.
• Executive control network (dorsolaterale prefrontal and parietal regions). During stress, this network is downregulated.

Dynamically shifting neural resources within these large-scale networks facilitates adaptive stress responses. Following stress, resources are allocated to the executive control network, downregulating the salience network. Disruption in this neural equilibrium have been linked to post-traumatic stress disorder, depression, bipolar disorder, anxiety, and schizophrenia.  

What effects does neonatal stress have on fetal brain development?

Exposure to neonatal stress appears to be associated with alterations in several structures. There seems to be a developmental period of increased sensitivity to stress, affecting stress-regulatory networks. Research has uncovered the following:

• An association between high stress and decreased frontal and parietal brain volumes.
• Alterations in white matter microstructure in the temporal lobes in preterm born infants related to stress.
• Invasive procedures were associated with reduced white matter and subcortical gray matter maturation in preterm neonates.

How can prematurity cause later life resilience and vulnerability?

• Prematurity often leads to alterations in normal autonomic development, which is essential for respiratory and cardiovascular homeostasis. ANS dysfunction following prematurity persists into infancy and later life, possibly through functional deficiencies of the vagus.
• Neonatal adversity impacts neuroendocrine development. Chronic stress can downregulate cortisol production and thereby reduce the detrimental effects of glucocorticoids. Alterations in HPA-axis functioning persist into adulthood. Also, during HPA-axis development there is a shift between hypo- and hyper-reactivity of the HPA-axis. Postnatal stress possibly alters the set-point of HPA-axis functioning in preterm-born individuals.
• Genetic and epigenetic variation plays a role in the long-term effects of early life stress. Epigenetic markers are developmentally sensitive to the quality of the pre- and post-natal environment. Early adversity can produce lasting epigenetic modifications.

What is the Polyvagal theory?

The Polyvagal theory states that alterations in vagal tone and reactivity (i.e. parasympathetic regulation) can lead to the development of psychiatric disorders in preterm-born individuals. The theory assumes three phylogenetic stages that underlie different behavioral responses: social communication, mobilization, and immobilization.

Which non-pharmacological interventions are recommended to support postnatal brain development for preterm-born infants?

Several interventions have the potential to adversely impact the developing postnatal brain by altering neuronal processing:

• Skin-to-skin contact may reduce infants´ stress while in the hospital. Skin-to-skin care is related to lower stress reactivity, improved white matter microstructural development, and reduced saliva cortisol levels. Also, it positively affects mother´s mood, reduces parental stress levels, and increases parental attachment behavior, possibly positively affecting the preterm infant´s stress-regulatory capacities.
• Music, massage, co-bedding, and Family Nurture Interventions are linked to improvement in HPA-axis functioning and autonomic control. It is a form of environmental enrichment that possibly stimulates cortical plasticity and attenuates the stress response of preterm infants.
• Single-family rooms may reduce infant and parental stress and increase parental involvement.