Antenatal Opioid Exposure—Discovery of a Broad Spectrum of Impaired Brain Development in Affected Newborns 

January 2026

Introduction

Opioid use among pregnant women and the consequences to the developing fetus are enormous public health issues worldwide, especially in the United States.^1-4 In the US, the prevalence of opioid use during pregnancy more than quadrupled from 1999-2014 (from 1.5 per 100 delivery hospitalizations to 6.5). Approximately 60-80% of such infants will develop some manifestations of a neonatal withdrawal syndrome, but of particular importance for this Commentary, subsequently, offspring exhibit a broad spectrum of neurodevelopmental deficits (see later), involving cognition, motor function, visual function, language, and social behavior.^1,3,5-7 Although issues related to infancy and childhood, e.g., nutrition and such socio-economic challenges as ongoing drug use, parental dysfunction, and poverty, complicate attribution of these deficits to prenatal opioid exposure per se, the balance of data indicates that these sequelae do relate in large part to the prenatal opioid exposure.

This Commentary was stimulated by a recent report, available online as an accepted pre-proof,⁸ that provides major insight into the connectivity disturbances detectable in newborns with antenatal exposure to opioids. In the following, I will review briefly the neurodevelopmental impairments documented in infants exposed antenatally to opioids, and the results of previous studies of such infants by structural and functional MRI. The findings of the recent report by De Asis-Cruz et al.⁸ then will be described, followed by my view of the likely neurobiological underpinnings of the findings and the implications for follow-up of the affected infant.

Neurodevelopmental Impairment in Infants Exposed to Opiates in Utero

A broad spectrum of neurodevelopmental impairments has been delineated in infants exposed to opiates in utero. Concerning cognition, although opioid-exposed infants tend to exhibit cognitive function within the normal range, one large review noted that such infants had mean scores approximately 10 points below control infants on standardized cognitive tests.⁹ Particular involvement of executive function has been documented. Additionally, behavioral issues are common. These include attentional deficits, hyperactivity and impulsivity. Behavioral issues may increase with age. Impairments of motor and visual function have been emphasized.¹ The visual function disturbances are reminiscent of cerebral visual impairment (see¹⁰), but more data are needed. Although beyond the scope of this Commentary to outline the various sequelae in detail, the important point is to recognize the apparent relation of these deficits to multiple regions of the developing central nervous system (see later).

Major Current Challenge for Neonatology: Identification of the Infant at Highest Risk for Adverse Outcome after Antenatal Exposure to Opioids

The emphasis of this Commentary is identification of the newborn with antenatal opioid exposure who is at highest risk for the subsequent neurodevelopmental impairments described in the previous section. Such identified infants then could be targeted for careful, broad-based follow-up, with emphasis on cognitive, visual, motor, social and behavioral development. Specific interventions then could be applied early and intensively. Previous work has utilized structural and functional MRI approaches as outlined next.

Structural MRI Features of Infants Exposed to Opiates

A relatively small series of MRI studies have focused on structural features in antenatal opioid-exposed infants.^11-19 The principal abnormalities have included decreased volumes in  multiple cerebral regions, basal ganglia, thalamus, brainstem and cerebellum, as well as evidence for altered maturation of multiple cerebral white matter tracts. The relative consistency of the findings is noteworthy. However, sample sizes often have not been large, control groups have varied in degree of characterization, and the MR methodologies have varied in sophistication.

The largest and most detailed study of the effects of antenatal opioid exposure on global and regional brain volumes was derived from the large OBOE (Outcomes of Babies with Opioid Exposure) study and reported recently by Limperopoulos and coworkers.²⁰ Utilizing 3T MRI and studying 173 exposed newborns and 96 unexposed controls, the investigators identified in the opioid-exposed group smaller volumes of total brain, cerebral cortex, cerebral white matter, deep gray matter, amygdala, brainstem, and cerebellum.

Taken together, the structural MRI data suggest widespread disturbances of brain development. These findings lead to the critical issue of their relation to the functional impact of these impairments, as discussed next.

Functional MRI Features of Infants Antenatally Exposed to Opiates: Previous Studies

Several relatively recent reports have focused on functional connectivity in antenatal opioid-exposed infants.^21-25 Although the numbers of infants studied have been generally small (n=10 to n=42), and most infants have been several weeks or more postnatal at the time of MRI assessment, the findings are of interest. Principal deficits in opioid-exposed infants involved connectivity in thalamic-cortical networks, limbic and subcortical networks, visual networks, and global functional networks. Collectively, the findings suggest widespread impairment of functional connectivity, involving multiple and varied brain networks. Moreover, taken as a group, the findings of these previous studies delineate deficits that correlate with the subsequent cognitive, behavioral and social deficits documented on follow-up of opioid-exposed infants. However, the earlier work requires elaboration and confirmation in a large, controlled study with a comprehensive assessment of a broader array of brain circuits than previously described (see next).

Functional MRI Features of Infants Antenatally Exposed to Opiates: Current Study

The focus of this Commentary is a recent study accepted for publication in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging and available currently as a pre-proof.⁸ Functional MRI data were obtained from 3T MRIs at four centers as part of a prospective study of outcomes of infants exposed antenatally to opioids. Exposure occurred in the second and/or third trimester and was documented by positive urine toxicology screen at delivery and/or maternal history. The opioids most responsible for exposure were buprenorphine (69%) and methadone (25%). Infants were born between 37 and 42 weeks gestational age and were scanned between 38 and 49 weeks postmenstrual age. Functional connectivity was assessed in fully 93 brain regions. A total of 248 scans (158 opioid-exposed and 90 unexposed) were obtained.

Principal fMRI Findings

The notable findings were (1) relatively preserved connectivity in canonical sensorimotor and higher-order resting state networks, but (2) widespread alterations in cortical and subcortical circuits in the infants antenatally exposed to opioids. These alterations involved limbic, paralimbic, peri-opercular, occipital and prefrontal cortices and were similar in the methadone- and buprenorphine-exposed groups.

Relation of Regional Connectivity Disturbances to Subsequent Clinical Features

The fMRI findings of De Asis-Cruz et al.⁸ are considered best as those exhibiting hypoconnectivity and those exhibiting hyperconnectivity. As I will note, relations to the subsequent neurologic abnormalities observed in antenatally opioid-exposed infants are apparent.

Hypoconnectivity was noted in cortico-cerebellar and fronto-limbic pathways. As noted by De Asis-Cruz et al., in view of the well-documented role for cortico-cerebellar pathways in sensorimotor integration, motor learning and postural regulation, the impaired connectivity likely relates to the long-term motor deficits well-documented in these infants.^3,8,9 Moreover, recent work implicates cortico-cerebellar circuitry in emotional memory and social cognition,^26,27 again, deficits later observed in opioid-exposed infants. Additionally, hypoconnectivity in fronto-limbic circuits, important for behavioral/emotional regulation, could relate to subsequent deficits in cognitive/affective interactions and behavioral/emotional regulation, phenomena likely involved in the increased risk in antenatally exposed infants for such subsequent conditions as conduct disorders and ADHD.⁸

Interestingly, hyperconnectivity was noted in several circuits in the opioid-exposed newborns.⁸ The regions particularly involved included limbic/paralimbic regions (amygdala, orbitofrontal gyri, peri-opercular and parietal association cortex) and superior occipital/parietal regions. These disturbances could relate to the heightened reactivity to environmental stimuli in the newborn period (as part of the neonatal opioid withdrawal syndrome). Perhaps more importantly, these alterations could relate to later disturbances in social perception, empathy, language processing and visual disturbances.^8,28,29

The widespread presence of both hypo- and hyperconnectivity likely is at the root of the cognitive, emotional and behavioral abnormalities observed subsequently in opioid-exposed infants. The combined presence of these connectivity abnormalities raises important questions about the developmental neurobiological events disturbed in this context, as discussed next.

Neurobiological Disturbances Caused by Antenatal Exposure to Opioids

Insight into the potential neurobiological bases for the connectivity disturbances described in the opioid-exposed infants is perhaps best addressed by considering (1) the principal developmental events occurring in human brain during the likely time period of opioid exposure, and (2) the clues from experimental studies of the deleterious effects of opioids on brain developmental events.

Principal Brain Developmental Events During Antenatal Opioid Exposure

The developmental period complicated by opioid exposure in the largest, controlled study⁸ encompasses the second and third trimesters of pregnancy. The major developmental events in brain during these critical periods involve cerebellum, brainstem, thalamus, basal ganglia, cerebral white matter and cerebral cortex (see^30-35 for reviews). It is beyond the scope of this Commentary to review the details of these events. To summarize briefly, the principal components and events involve neuronal proliferation and migration in cerebellum; axonal development and outgrowth in brainstem, thalamus, basal ganglia and cerebrum; widespread proliferation and differentiation of oligodendroglial precursors; axonal ensheathment by premyelinating oligodendrocytes; onset of myelination in brainstem and diencephalic structures; development of thalamocortical connections; elaboration of cerebral cortical dendrites; development of cortico-cortico and callosal axonal connections; and onset of synaptogenesis in multiple cerebral regions (see³⁵ for review). A consequence of these events is the development of functional connectivity throughout the central nervous system, as illustrated by the functional MRI studies referred to earlier. Widespread impairment of connectivity as shown in the fMRI studies described earlier suggests that opioids have deleterious effects on many of these aspects of human brain development. Are there experimental data to help delineate the specific cellular and molecular events affected by opioids and underlying the diffuse developmental impairments?

Principal Effects of Antenatal Opioid Exposure on Brain Development: Relevant Experimental Studies

Experimental studies provide important insights into the likely neurobiological bases for the widespread connectivity defects described earlier. The most likely targets appear to be neuronal progenitors, astrocytes, and developing oligodendrocytes, as discussed briefly next.

Concerning neuronal progenitors, several studies using model systems indicate that opioids inhibit neuronal progenitor cell proliferation and neuronal migration, and enhance neuronal apoptosis.^36-39 Such effects could be involved in the observations in antenatally exposed infants of decreased volumes of cerebellum (see earlier). (Recall that neuronal proliferation is very active in the external granule cell layer of the cerebellum in the second and third trimesters of gestation.⁴⁰) A related and perhaps important effect related more directly to connectivity impairment is a negative impact of opioids on astrocytes that results in impaired neuronal synaptic development.⁴¹

Impairments by opioids of oligodendroglial development may be of particular relevance to the human fetus. Thus, oligodendroglial cells express opioid receptors throughout their development.^42-44 The principal opioid receptors involved are the mu (µ) and kappa (κ) receptors. Although more data are needed, the principal deleterious effects of opioid exposure in experimental models include impaired oligodendroglial maturation with, as consequences, impairments of axonal-glial interactions and subsequently myelination. These effects could explain the impaired white matter development observed in antenatally opioid-exposed infants. A failure of normal ensheathment of axons by developing oligodendrocytes would be expected to lead to impaired axonal growth and function.³⁵ Impaired axonal function would be expected to lead to altered thalamic and cerebral cortical development via anterograde and retrograde effects.³⁵ (Recall, as noted earlier, that antenatally exposed infants exhibit decreased volumes of thalamic and cerebral cortex.) Finally, because synaptogenesis is a major consequence of axonal contact and function, a disturbance of connectivity would be expected.

Conclusions

The fMRI observations of Limperopoulos and coworkers⁸ indicate that widespread impairments of connectivity constitute the principal deleterious result of antenatal opioid exposure. The structural accompaniments of the fMRI data (see, especially, Wu et al.²⁰) are consistent with such widespread impairment. Although more detailed experimental studies are needed, available data indicate that the principal deleterious effects of opioids are exerted on neuronal progenitors, astrocytes, developing oligodendrocytes and axons. Subsequent neurodevelopmental deficits almost certainly relate to the structural and especially the connectivity deficits, as defined earlier.

In my view, the clinical implications are many. Certainly, the antenatal challenges related to causation of antenatal opioid exposure are paramount to address and are beyond the scope of this Commentary. Perhaps of greatest current importance to the neonatologist is recognition of the affected infant in the newborn period. Connectivity studies, as carried out by Limperopoulos and coworkers,⁸ clearly are ideal. The technology needed for such studies is not widely available, but with the field moving rapidly, nearly comparable MRI insights should be attainable. In the interim, careful volumetric studies, more readily available, may provide valuable information as described earlier.

Perhaps of greatest importance, the findings of the current work indicate that the infant exposed antenatally to opioids should be followed very carefully. As alluded to earlier, potential interventions to be needed will include developmental, visual, nutritional, experiential, parenting, and educational areas, among others.^35,45

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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