Massive Burden of Neuropsychiatric Sequelae after Very Preterm Birth— Evolving Understanding of Neurobiology and Potential Interventions

March 2025

Introduction

Despite the high frequency and large absolute number of affected infants and children with neurobehavioral and neuropsychiatric disorders related to perinatal factors, there is a relative paucity of data concerning the brain abnormalities underlying these disorders, the means of detection in the neonatal period, and the best preventative/ameliorative approaches. Preterm infants comprise a large proportion of this affected group. A large literature has addressed the frequency and severity of neuropsychiatric disorders in survivors of very preterm birth.^1-7 A particularly well characterized group of 177 very preterm infants followed to 7 years of age had, compared to term-born infants, three times the odds of meeting criteria for any psychiatric diagnosis at age 7 years.⁷ The most common diagnoses were anxiety disorders (11%), attention deficit-hyperactivity disorder (10%), and autism spectrum disorder (ASD) (4.5%). The relation to ASD has been documented in other studies and has ranged generally from 5-10%.^1,3,6 To what extent the improvement in survival rates of very preterm infants accounts for the nearly doubling of prevalence of ASD in the United States over the past two decades is unclear but noteworthy.⁴ In the United States, approximately 55,000 very preterm infants survive the newborn period yearly,^8,9 and thus a rough approximation would be that at least 2,500-5,000 new cases of significant neuropsychiatric disorders, including ASD, result yearly in such infants.

The pathogenesis and neuropathology underlying the subsequent neuropsychiatric disorders in very preterm infants remain to be defined fully. Suffice it to say here, the preponderance of information suggests that development of cortico-limbic connections and particularly their relation to the development of the central autonomic network (CAN) are of central importance.^10-15

Thus, this Commentary will address the three great current challenges in neonatology in this area: (1) detection in the newborn period of the infant most likely to develop later neuropsychiatric phenomena, (2) identification of the neuroanatomic/neuropathological substrate, and (3) prevention or amelioration of the subsequent disabling syndromes. The presentation was stimulated by a recent report¹⁶ and by several related studies (see later) that provide critical insight into the first two of these challenges. However, before addressing these studies directly, I will summarize briefly the anatomy and function of the neural networks that appear to be affected in premature infants who later develop the neuropsychiatric phenomena.

Central Autonomic Network-Limbic Anatomy and Function

The central autonomic network (CAN) and its associated limbic connections are central to the occurrence of neuropsychiatric phenomena after premature birth (see, for review,¹⁰). The anatomy, development and function of the CAN and, in particular, its limbic connections are difficult to summarize succinctly, but I will attempt to do so in what follows.

Central Autonomic Network

The principal components of the CAN include an interconnected group of cortical (e.g., insular cortex), subcortical (e.g., several hypothalamic nuclei, thalamus), and brainstem (dorsal motor nucleus of the vagus, nucleus ambiguus, nucleus of the solitary tract) structures that modulate the autonomic nervous system.^16,17 (“Fight or flight” or “playing dead” responses or alterations in heart rate/variability or respiratory effort are recognized autonomic responses mediated at brainstem and spinal cord levels.¹⁰) Importantly, in the context of this presentation, the CAN has important connections to central limbic structures and initiates signals that impact emotion, affect, decision making and social behavior.¹⁷

CAN-Limbic Interactions

The critical limbic structures interacting with the CAN include the amygdala, hippocampus, cingulate gyrus, hypothalamus and thalamus (for illustration, see Fig. 2 in¹⁰ and Fig. 1 in¹⁶). The multiple connections to the CAN develop early in brain development. These limbic system connections exhibit considerable plasticity and can be strengthened or weakened from early in brain development to postnatal life by a myriad of intrinsic and extrinsic factors (see later). Disturbances of this constellation of the CAN and its limbic system connections by factors associated with prematurity can have enduring adverse effects on behavioral development, including serious neuropsychiatric phenomena.

Prematurity and CAN and Limbic Connectivity

The recent report that stimulated this Commentary is entitled “Third Trimester Development of Central Autonomic Network Connectivity is Altered in an Extrauterine Environment.”¹⁶ The aims of the study were (1) to utilize resting state functional MRI (fMRI)  to compare CAN connectivity in preterm infants (average gestational age 29 weeks) at term-equivalent age (TEA) with term-born controls, (2) to characterize third trimester CAN development in preterm infants, and (3) to assess the relationship of CAN connectivity in the preterm infants with their developmental outcomes at 18 months corrected age.

Notable findings were that CAN connectivity at TEA was not associated with connectivity on the initial scan nor with gestational age at birth, an observation that suggests maturation of CAN is likely influenced by subsequent factors in the extrauterine environment.¹⁶ This observation suggests that the extrauterine period presents not only a time of disturbance of CAN development but also a time for beneficial intervention.

CAN connectivity at TEA was significantly higher in the term than in the preterm infants in multiple key areas, i.e., amygdala, hippocampus, insula, thalamus and brainstem.¹⁶ Previous studies also have shown reduced connectivity in these areas in preterm infants at TEA.^14,18 Moreover, neonatal stress in preterm infants (number of painful procedures) has been shown to be associated with such reduced connectivity (see later).¹⁸ Importantly, in the current report and previous studies identifying the connectivity disturbances, behavioral abnormalities, especially externalizing behaviors, have been observed on follow-up.^{13,15,16,18,19} Such behavioral abnormalities have been characterized later as aggression, disruptive behavior, impaired impulse control, hyperactivity, and inattention.²⁰ Thus, connectivity studies as outlined in these reports potentially could identify, at TEA, infants at particular risk for development of such behaviors and lead to early institution of targeted therapies for their prevention or amelioration (see later).

Mechanisms Underlying the Relations Between Prematurity and Aberrant CAN-Limbic Development

The neuroanatomic and neuropathological bases for the relations between prematurity and aberrant CAN-limbic development likely are multiple. Available data indicate that the specific developmental events operative during this period are diverse, depending upon the region. For example, active developmental events in the hippocampus in the preterm period include the final phases of neurogenesis and neuronal migration; dendritic development and early stages of synaptogenesis are prominent.^21,22 Pre-oligodendroglial maturation, ensheathment of axons and very early stages of myelination are also underway.^23,24 Myelination does not become especially prominent until postnatally.²⁴ Sophisticated MRI studies also document axonal development in limbic areas, especially including amygdala and related limbic connections.^11,25 Multiple studies have shown that prematurity is associated with various impairments of these events.^{11,16,21,22,25-30} Such frequent insults to premature infants as hypoxia-ischemia and inflammation could play a causative dysmaturational role.²⁸ These factors could not be implicated specifically in the work of Christoffel et al.,¹⁶ but total numbers studied were relatively small. In the large-scale study of Treyvaud et al. noted earlier,⁷ prominent MRI brain abnormality was predictive of later psychiatric disorder (adjusted OR=5.63) but such MRI abnormality accounted for only 12% of the infants with later neuropsychiatric disorder.

Although, as just noted, multiple overt insults have been well documented to impair the developmental events active in limbic areas during the premature period, less overt occurrences, especially prenatal and neonatal infant stress, are among prominent effectors of such impairment.^{10,18,26,31,32} More data clearly are needed. I favor the notion that the impairments of development of the CAN and its limbic connections are dysmaturational events related to a wide variety of effectors, ranging from prenatal, neonatal and postnatal.

Interventions to Improve Neuropsychiatric Outcomes and to Promote CAN-Limbic Development in Very Preterm Infants

Because CAN-limbic dysmaturation appears to be central to the neuropsychiatric disorders later observed in very preterm infants, the critical next challenge is to devise interventions to prevent or ameliorate this disturbance. A large corpus of research has addressed this general area. In the following, I will briefly summarize interventions according to the timing of the dysmaturational influences, i.e., prenatal, neonatal and postnatal.

Prenatal Interventions

The best studied prenatal interventions relate to the deleterious effect of prenatal stress on development of CAN-limbic connections.^10,32 The general importance of prenatal stress on developing brain and subsequent neuropsychiatric disorders, such as ASD, attention deficit-hyperactivity disorder, etc., is enormous (see, for review,³¹). Important prenatal stress exposures include anxiety and depression. For example, approximately 8-23% of newborns in the United States (or as many as 800,000) experience prenatal exposure to depression, and similarly large numbers are exposed to anxiety.³¹ Prenatal stress can lead to fetal autonomic changes, e.g., fetal heart rate, activity, sleep patterns, cerebral blood flow velocity.³³ Importantly, such stress can also lead to altered brain development.

Although mechanisms by which prenatal stress leads to altered brain development are multiple, the best documented involve elevations in glucocorticoids.³⁴ Of potential relevance in this context is the recent large study from Denmark that showed an increase in ASD among mothers treated with glucocorticoids for risk of preterm delivery or for autoimmune or inflammatory disorders.³⁵ The hippocampus, amygdala, and prefrontal cortex, key areas in the CAN-limbic network, are rich in glucocorticoid receptors, which bind the stress-induced glucocorticoids and thereby lead to altered structure and function. An especially informative group of studies relevant to prenatal stress and brain development utilized a measure of “prenatal disadvantage” (PND)³² that includes measures of mother’s income-to-needs ratio, educational attainment, area deprivation index, insurance status and nutrition. Volumetric MRI studies showed a negative relationship between PND and bilateral amygdala and hippocampal volumes, and by functional MRI, between amygdala-prefrontal cortex connectivity.^32,36 These observations suggest that interventions that reduce prenatal stress could improve autonomic-limbic development.

A potential role for specific nutrients in promoting CAN-limbic development is suggested by several studies (see for review¹⁰). Nutrients of potential importance include folic acid and zinc, among others.

Neonatal and Subsequent Interventions

Neonatal and subsequent interventions for the very preterm infant focused on optimizing CAN-limbic development are highly desirable because, as noted earlier, CAN-limbic development is highly plastic during these periods. A particularly compelling study of 145 premature infants showed the importance of postnatal stress (number of invasive procedures) and, by extrapolation, reduction of such stress on connectivity growth.¹⁸ Higher stress levels impaired structural connectivity growth in areas particularly involved in CAN-limbic connections, i.e., especially insula, cingulate cortex, hippocampus and amygdala. Greater affection of this connectivity was associated with more internalizing symptoms at two to five years. The likely value of minimization of such stress on CAN-limbic development seems apparent.

A variety of other approaches for stress reduction (e.g., enhanced maternal-infant interactions, kangaroo care; maternal voice, speech, singing; music, etc.) have been shown to promote in the infants autonomic stability and in some cases improved brain developmental parameters.^25,37,38 In one such study, a specially composed music intervention in very preterm infants showed at TEA larger amygdala volumes (among other developmental parameters).²⁵

Beyond the neonatal period, a number of interventions in very preterm infants have focused on mitigating stress and emotional distress and on sensitive and responsive parenting.^30,39 Managing the stresses provoked by social disadvantage appears to be a particularly fertile area for future research, especially regarding the effects on subsequent CAN-limbic development.³²

Conclusions

This Commentary has been addressed to the broad problem of neurobehavioral / neuropsychiatric disorders that develop in survivors of very preterm birth. The focus has been (1) the neuroanatomic/neuropathological substrate for those disorders, (2) the means of their detection in the newborn period, and (3) potential preventative or ameliorative interventions. The anatomic substrate affected in these disorders appears to be principally the developing CAN and its limbic connections. The neuropathological underpinning is not known decisively, but likely involves dysmaturation of multiple developmental events, including neuronal differentiation, axonal outgrowth, pre-oligodendroglial maturation and connectivity development. The means of detection in the newborn period involves, especially, measures of connectivity by functional MRI, the latter more and more available with modern-day instruments and personnel. The means of prevention/amelioration of the later functional effects are almost certainly as diverse as stress reduction at both maternal (prenatal and postnatal) and neonatal levels, nutritional optimization, and enhanced mother-infant interactions, among others. In my view, this burgeoning field of study is of great importance.

Joseph J. Volpe, MD

Department of Neurology, Boston Children’s Hospital

Bronson Crothers Professor of Neurology, Emeritus, Harvard Medical School

Boston MA

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