Antenatal Opioid Exposure and Global and Regional Brain Volumes in Newborns

Yao Wu; Stephanie L Merhar; Carla M Bann; Jamie E Newman; Kushal Kapse; Josepheen De Asis-Cruz; Nicole Mack; Sara B De Mauro; Namasivayam Ambalavanan; Jonathan M Davis; Scott A Lorch; Deanne Wilson-Costello; Brenda B Poindexter; Myriam Peralta-Carcelen; Catherine Limperopoulos

doi:10.1001/jamapediatrics.2025.0277

. 2025 Apr 7;179(6):639–646. doi: 10.1001/jamapediatrics.2025.0277

Antenatal Opioid Exposure and Global and Regional Brain Volumes in Newborns

Yao Wu ¹, Stephanie L Merhar ^2,³, Carla M Bann ⁴, Jamie E Newman ⁴, Kushal Kapse ¹, Josepheen De Asis-Cruz ¹, Nicole Mack ⁴, Sara B De Mauro ^5,⁶, Namasivayam Ambalavanan ⁷, Jonathan M Davis ⁸, Scott A Lorch ^5,⁶, Deanne Wilson-Costello ⁹, Brenda B Poindexter ¹⁰, Myriam Peralta-Carcelen ⁷, Catherine Limperopoulos ^1,^✉

¹Developing Brain Institute, Children’s National Hospital, Washington, DC

²Perinatal Institute, Division of Neonatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

³Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio

⁴Analytics Division, RTI International, Research Triangle Park, North Carolina

⁵Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

⁶University of Pennsylvania Perelman School of Medicine, Philadelphia

⁷University of Alabama at Birmingham

⁸Tufts University, Boston, Massachusetts

⁹Case Western Reserve University, Cleveland, Ohio

¹⁰Emory University, Atlanta, Georgia

Accepted for Publication: January 2, 2025.

Published Online: April 7, 2025. doi:10.1001/jamapediatrics.2025.0277

^✉

Corresponding Author: Catherine Limperopoulos, PhD, Center for Prenatal, Neonatal & Maternal Health Research, Children’s National Hospital, 111 Michigan Ave NW, Washington, DC 20010 (climpero@childrensnational.org).

Author Contributions: Drs Wu, Merhar, and Limperopoulos had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Wu and Merhar contributed equally to this work.

Concept and design: Merhar, Bann, Newman, DeMauro, Davis, Wilson-Costello, Limperopoulos.

Acquisition, analysis, or interpretation of data: Wu, Merhar, Kapse, De Asis-Cruz, Mack, DeMauro, Ambalavanan, Lorch, Wilson-Costello, Poindexter, Peralta-Carcelen, Limperopoulos.

Drafting of the manuscript: Wu, Merhar, Davis.

Critical review of the manuscript for important intellectual content: Wu, Bann, Newman, Kapse, De Asis-Cruz, Mack, DeMauro, Ambalavanan, Davis, Lorch, Wilson-Costello, Poindexter, Peralta-Carcelen, Limperopoulos.

Statistical analysis: Wu, Mack, Limperopoulos.

Obtained funding: Merhar, Bann, Newman, Ambalavanan, Lorch, Poindexter.

Administrative, technical, or material support: Wu, Merhar, Bann, Newman, De Asis-Cruz, Davis, Wilson-Costello, Limperopoulos.

Supervision: Merhar, Newman, Davis, Wilson-Costello, Poindexter, Peralta-Carcelen, Limperopoulos.

Conflict of Interest Disclosures: Dr Merhar reported grants from the US National Institutes of Health (NIH) during the conduct of the study. Drs Bann and Newman reported grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) during the conduct of the study. Dr DeMauro reported grants from the NIH during the conduct of the study and outside the submitted work. Drs Ambalavanan, Davis, and Lorch reported grants from the NIH during the conduct of the study. Dr Peralta-Carcelen reported grants from NICHD during the conduct of the study and NICHD/RTI funding for the study that produced this work. No other disclosures were reported.

Funding/Support: This study was supported by the US National Institutes of Health (NIH) through the NIH HEAL Initiative under award numbers 1PL1HD101059-01, 1RL1HD104251-01, 1RL1HD104252-01, 1RL1HD104253-01, and 1RL1HD104254-01.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We are indebted to the infants and their families who agreed to take part in this study; to our medical and nursing colleagues at Case Western Reserve University, Cincinnati Children’s Hospital Medical Center, University of Alabama at Birmingham, and Children’s Hospital of Philadelphia; to our neuroimaging core colleagues at Children’s National; and to our data coordinating center staff at RTI International.

^✉

Corresponding author.

PMCID: PMC11976647 PMID: 40193106

Key Points

Question

Do brain volumes differ in opioid-exposed vs unexposed newborns?

Findings

In this cohort study among 173 term newborns with antenatal opioid exposure and 96 unexposed controls, opioid-exposed newborns had smaller total brain volumes and volumes of cortical and deep gray matter, white matter, cerebellum, brainstem, and amygdala compared to controls on magnetic resonance imaging. Methadone-exposed newborns had smaller white matter volumes, while buprenorphine-exposed newborns had smaller right amygdala volumes; polysubstance-exposed newborns had smaller volumes in more brain regions than opioid-only exposed newborns.

Meaning

Antenatal opioid exposure is associated with smaller neonatal brain volumes, with varying impact depending on the type and number of exposures.

Abstract

Importance

Although antenatal opioid exposure is associated with impaired brain growth, previous studies are limited by small sample sizes and lack of controls. As a result, the impacts of opioid exposure on the developing brain remain poorly understood.

Objective

To compare global, regional, and tissue-specific brain volumes in opioid-exposed newborns vs unexposed controls.

Design, Setting, and Participants

In the OBOE (Outcomes of Babies with Opioid Exposure) study, term newborns with antenatal opioid exposure and unexposed controls were recruited at 4 sites in the US from August 2020 to December 2023. Data analysis was performed from August 2020 to December 2024.

Main Outcomes and Measures

The primary outcome was brain volumes in both groups, assessed via unsedated 3-dimensional (3-D) volumetric magnetic resonance imaging (MRI) in opioid-exposed and unexposed newborns prior to 8 weeks of age. T2-weighted MRI data were acquired on Siemens and Philips 3T scanners and harmonized across sites. Brains were segmented using DrawEM- and 3D U-Net–based pipelines and manual corrections. Brain volumes were compared between groups using analysis of covariance, adjusting for postmenstrual age at MRI, sex, birth weight, maternal smoking, and maternal education.

Results

A total of 173 newborns with antenatal opioid exposure and 96 unexposed controls were studied. MRIs were performed at a mean (SD) age of 42.84 (2.11) postmenstrual weeks, and 117 newborns (43.5%) were female. The opioid-exposed group had significantly smaller total brain volume (387.51 vs 407.06 cm³; difference, 19.55; 95% CI, 8.75-30.35) and cortical (167.07 vs 176.35 cm³; difference, 9.28; 95% CI, 3.86-14.70), deep gray matter (27.22 vs 28.76 cm³; difference, 1.54; 95% CI, 0.66-2.43), white matter (159.90 vs 166.65 cm³; difference, 6.76; 95% CI, 1.71-11.81), cerebellar (23.47 vs 24.99 cm³; difference, 1.52; 95% CI, 0.67-2.36), brainstem (6.80 vs 7.18 cm³; difference, 0.38; 95% CI, 0.19-0.57), and amygdala volumes (left: 0.48 vs 0.51 cm³; difference, 0.03; 95% CI, 0.004-0.05; right: 0.51 vs 0.55 cm³; difference, 0.04; 95% CI, 0.08-0.07) compared to controls. Methadone-exposed newborns showed significantly smaller white matter volume compared to controls, while buprenorphine-exposed newborns showed significantly smaller right amygdala volume than controls. Compared to controls, newborns exposed to opioids only and those exposed to opioids plus other substances both showed significant reductions in volumes of cortical and deep gray matter, cerebellum, brainstem, right amygdala, and total brain. Polysubstance-exposed newborns additionally showed smaller volumes in white matter and the left amygdala compared to controls.

Conclusions and Relevance

In a large cohort of antenatally opioid-exposed newborns, there were significant reductions in global and regional brain volumes compared to unexposed controls. These data suggest vulnerability of the developing brain to antenatal opioid exposure, with varying effects depending on the type and number of substances.

Trial Registration

ClinicalTrials.gov Identifier: NCT04149509

This cohort study using data from the OBOE (Outcomes of Babies with Opioid Exposure) study compares global, regional, and tissue-specific brain volumes in opioid-exposed newborns vs unexposed controls.

Introduction

Antenatal opioid exposure continues to be an urgent problem in the US, with approximately 7% of pregnant women reporting opioid use during pregnancy.¹ Opioids readily cross the placenta and can impact the developing brain. Animal studies suggest a direct effect of maternal opioid administration on fetal brain development, with studies in rodents showing altered myelination after prenatal exposure to buprenorphine² or methadone,³ decreased neurogenesis after exposure to buprenorphine,⁴ and increased neuroinflammation following exposure to methadone.⁵ In humans, antenatal opioid exposure has been associated with adverse neurodevelopmental consequences, including lower cognitive and language scores,^6,7 higher rates of attention-deficit/hyperactivity disorder, and difficulties with executive function.⁸ However, it is uncertain whether this association is due to direct adverse effects of opioids on the brain or other confounding factors (eg, socioeconomic status, polysubstance exposure, parenting, genetics). In some studies, the effects of antenatal opioid exposure on brain development are no longer significant after controlling for social and environmental risk factors.^9,10

Studies in older children and adolescents exposed to antenatal opioids have shown smaller brain volumes in several regions. Only 2 small studies have been published evaluating brain volumes in infants exposed to antenatal opioids,^11,12 which demonstrated reduced total brain and deep gray matter volumes in the exposed group. However, these studies were unable to account for important potential confounders. Studies that incorporate larger cohorts, a well-matched control group, and neuroimaging soon after birth are needed to more accurately elucidate the direct effect of opioids on the developing brain. In the OBOE (Outcomes of Babies with Opioid Exposure) study,¹³ 3-dimensional (3-D) volumetric magnetic resonance imaging (MRI) scans were performed at 0 to 1 month of age in a cohort of term neonates with antenatal opioid exposure and unexposed control neonates. In this analysis, we evaluated whether there were differences in brain volumes between the exposed and unexposed groups and the effects of different types of opioid exposures and coexposures were examined. It was hypothesized that neonates with antenatal opioid exposure would have smaller global, regional, and tissue-specific brain volumes compared with unexposed controls.

Methods

Study Design

The ACT-NOW (Advancing Clinical Trials in Neonatal Opioid Withdrawal) OBOE study is a multisite, prospective observational study of newborns with prenatal opioid exposure and controls recruited from 4 sites in the US (NCT04149509). The OBOE study protocol is described in detail elsewhere.¹³ Families were approached for study participation prenatally in obstetric clinics or maternal substance use treatment programs or postnatally in the birth hospital. For the exposed group, neonates had to be exposed to opioids in the second or third trimester and born at 37 or more weeks’ gestation to be eligible for the study. For controls, neonates with no known or reported opioid exposure born 37 or more weeks’ gestation were eligible. Control participants were recruited from the same birth hospitals as exposed newborns, and control recruitment was targeted toward mothers with similar sociodemographic characteristics (specifically, nicotine use during pregnancy and public insurance). For both groups, neonates were excluded if they had known chromosomal or congenital anomalies with the potential to affect the central nervous system, 5-minute Apgar scores less than 5, any requirement for positive pressure ventilation in the neonatal intensive care unit, inability to return for outpatient MRI or follow-up, intrauterine growth restriction less than 3%, or if their birth mother reported significant alcohol use during pregnancy (≥8 alcoholic drinks/week). The initial study visit was scheduled prior to 8 weeks of age and included brain MRI and questionnaires for the mother or caregiver. Through a single institutional review board, the 4 OBOE study clinical sites, the neuroimaging core, and the data coordinating center received approval for human subject research activities, and written informed consent was obtained for all participants. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

Demographics

Race and ethnicity were assigned by review of the maternal electronic health record (EHR). Maternal age and insurance were also abstracted from the EHR. Maternal highest level of education was obtained from the neonate’s birth certificate. Neonatal demographic characteristics were abstracted from the newborn’s EHR.

Substance Use and Exposure

The newborn’s opioid exposure status needed for inclusion in the study was determined by maternal history, maternal urine toxicology screening at delivery, and/or neonatal urine, meconium, or umbilical cord toxicology screen. At the first visit, mothers completed a detailed substance use questionnaire asking about the type of substances used throughout pregnancy. Opioid-only exposure was defined as newborns exposed to opioids only, even if there were multiple opioid exposures (eg, fentanyl and buprenorphine). Polysubstance exposure was defined as exposure to opioids plus other psychoactive substances or medications, including cocaine, benzodiazepines, selective serotonin reuptake inhibitors, amphetamines, gabapentin, psychostimulants, muscle relaxants, tetrahydrocannabinol, and/or antipsychotics.

MRI Acquisition Protocol

3-D volumetric MRIs were performed during natural sleep. T2-weighted images were acquired on Siemens or Philips 3T scanners with protocols harmonized across the 4 clinical sites. Site 1 used a Philips 3T scanner with 32-channel head coil (Turbo Spin-Echo sequence; repetition time: 2500 milliseconds; echo time: 270 milliseconds; flip angle: 90°; image resolution: 0.982 × 0.982 × 1 mm³); site 2 used a Philips 3T scanner with 32-channel head coil (Turbo Spin-Echo sequence; repetition time: 2500 milliseconds; echo time: 251.65 milliseconds; flip angle: 90°; image resolution: 0.982 × 0.982 × 1 mm³); site 3 used a Siemens 3T scanner with 32-channel head coil (SPACE sequence; repetition time: 3200 milliseconds; echo time: 492 milliseconds; flip angle: 90°; image resolution: 0.982 × 0.982 × 1 mm³); and site 4 used a Siemens 3T scanner with 32-channel coil (SPACE sequence; repetition time: 3200 milliseconds; echo time: 492 milliseconds; flip angle: 90°; image resolution: 1 × 1 × 1 mm³).

Quantitative Volumetric MRI Analysis

Volumes (in cm³) of total brain, cortical gray matter, white matter, deep gray matter, cerebellum, brainstem, and left and right amygdala and hippocampus were quantifed (Figure). Cortical gray matter, white matter, deep gray matter, cerebellum, and brainstem were automatically segmented using Developing brain Region Annotation With Expectation-Maximization (Draw-EM) (Medical Image Registration ToolKit) pipelines.¹⁴ The left and right amygdala and hippocampus were automatically segmented using a 3D U-Net–based model,¹⁵ which was trained and validated using manual segmentations of 82 newborn brains at the Developing Brain Institute at Children’s National Hospital in Washington, DC. All brain structures were visually inspected and manually corrected by an experienced rater, and 40 of 269 total scans (14.9%) were randomly chosen and corrected by a second experienced rater. Interrater reliabilities using intraclass correlation coefficients for all measured regions were higher than 0.93. Raters were masked to exposure status and to each other’s manual corrections.

Figure. — Segmentation of a newborn brain at 42 postmenstrual weeks into cortical gray matter (green), white matter (blue), deep gray matter (gray), cerebellum (violet), brainstem (orange), amygdala (purple), left hippocampus (brown), and right hippocampus (red).

Statistical Analysis

Statistical analyses were performed using MATLAB 2024a (MathWorks) and SAS OnDemand for Academics (SAS Institute). Baseline and clinical characteristics of opioid-exposed newborns and unexposed controls were compared using t tests for continuous variables and Fisher exact tests for categorical variables. Brain volumes for newborns prenatally exposed to opioids vs unexposed controls were compared using analysis of covariance (ANCOVA), controlling for postmenstrual age at the time of MRI, sex, birth weight, maternal smoking status, and maternal education. Sex differences in brain volumes between opioid-exposed and unexposed groups were measured by including an interactions term (sex × exposure status) in the model. Brain volumes for newborns antenatally exposed to different types of opioids (methadone, buprenorphine, and other opioid types), as well as newborns exposed to only opioids vs opioids plus other substances vs unexposed controls, were compared using ANCOVA, controlling for postmenstrual age at MRI scan, sex, birth weight, maternal smoking status, and maternal education. P values were adjusted for multiple testing based on the false discovery rate according to the Benjamini-Hochberg method.¹⁶ Two-sided adjusted P values <.05 were considered statistically significant.

Results

Study Population

A flow diagram summarizing participant enrollment is shown in the eFigure in Supplement 1, and demographics are shown in Table 1. The final cohort consisted of 269 MRI scans performed in 173 opioid-exposed newborns (95 males, 78 females) and 96 unexposed controls (57 males, 39 females). Overall, 117 newborns (43.5%) were female. The mean (SD) [range] postmenstrual age at MRI was 42.81 (2.19) [37.42-48.00] weeks for opioid-exposed newborns and 42.90 (1.96) [38.00-48.42] weeks for unexposed newborns. Compared with controls, the opioid-exposed group had lower mean (SD) birth weight (3.18 [0.43] kg vs 3.41 [0.43] kg; P < .001) and head circumference at birth (34.03 [1.44] cm³ vs 34.68 [1.34] cm³; P < .001). Mean (SD) maternal age was higher (30.33 [4.37] years vs 28.31 [5.43] years; P = .002) and smoking was more common (134 smokers [77.5%] vs 22 smokers [22.9%]; P < .001) in the mothers of opioid-exposed infants. Conventional brain MRI studies were read by neuroradiologists masked to the exposure status of the infant. Punctate white matter abnormalities were more common in the newborns exposed to antenatal opioids compared to controls (26 [15.0%] vs 7 [7.3%]). In the exposed group, 2 newborns had mild Chiari 1 malformations, 3 had possible arachnoid cysts, 1 had a parafalcine cyst, and 8 had germinal matrix or choroid plexus hemorrhages or small amounts of intraventricular blood seen on MRI. In the control group, 1 newborn had unilateral optic nerve hypoplasia, 1 had a Chiari 1 malformation, and 1 had a small cerebellar vermis.

Table 1. Characteristics of the Study Cohort.

Characteristic	Newborns, No. (%)
Characteristic	Opioid-exposed (n = 173)	Unexposed (n = 96)
Sex
Female	78 (45.1)	39 (40.6)
Male	95 (54.9)	57 (59.4)
Maternal age, mean (SD), y	30.33 (4.37)	28.31 (5.43)
Maternal smoking during pregnancy	134 (77.5)	22 (22.9)
Birth weight, mean (SD), kg	3.18 (0.43)	3.41 (0.43)
Gestational age at birth, mean (SD), wk	39.06 (1.03)	39.26 (0.98)
Head circumference at birth, mean (SD), cm	34.03 (1.44)	34.68 (1.34)
1-min Apgar score, median (IQR)	8 (8-8)	8 (8-8)
5-min Apgar score, median (IQR)	9 (9-9)	9 (9-9)
Vaginal delivery	114 (66)	61 (66)
Postmenstrual age at MRI, mean (SD), wk	42.81 (2.19)	42.90 (1.96)
Maternal education
<High school	38 (22.0)	7 (7.3)
High school graduate	68 (39.3)	33 (34.4)
Partial college or specialized training	49 (28.3)	29 (30.2)
College or graduate degree	11 (6.4)	27 (28.1)
Unknown	7 (4.0)	0

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Abbreviation: MRI, magnetic resonance imaging.

Medications Used During Pregnancy

Table 2 summarizes the types of medications used during pregnancy, including buprenorphine, methadone, oxycodone, gabapentin, selective serotonin reuptake inhibitors, fentanyl, benzodiazepines, amphetamines, hydrocodone, psychostimulants, muscle relaxants, tetrahydrocannabinol, antipsychotics, and others. The most common opioids used during pregnancy were buprenorphine (68.8%) and methadone (26.0%).

Table 2. Self-Reported Maternal Medication Use During Pregnancy.

Medication	Newborns, No. (%)
Medication	Opioid-exposed (n = 173)	Unexposed (n = 96)
Buprenorphine	119 (68.8)	0
Tetrahydrocannabinol	66 (38.2)	3 (3.1%)
Methadone	45 (26.0)	0
Oxycodone^a	32 (18.5)	1 (1.0%)^b
Gabapentin	30 (17.3)	0
Selective serotonin reuptake inhibitors	27 (15.6)	16 (16.7%)
Benzodiazepines	27 (15.6)	2 (2.1%)
Fentanyl	20 (11.6)	0
Amphetamines	20 (11.6)	0
Antipsychotics	15 (8.7)	0
Muscle relaxants^b	11 (6.4)	5 (5.2%)
Psychostimulants^c	10 (5.8)	0
Hydrocodone	9 (5.2)	0
Hydromorphone	5 (2.9)	0
Heroin	3 (1.7)	0
Morphine	2 (1.2)	0
Cocaine	2 (1.2)	0
Other	24 (13.9)	2 (2.1%)

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^{^a}

One mother of a control newborn reported minimal oxycodone use after an injury in the second trimester. Maternal urine toxicology screen at delivery and newborn umbilical cord toxicology were negative for all substances.

^{^b}

Muscle relaxants included cyclobenzaprine.

^{^c}

Psychostimulants included Vyvanse (Takeda Pharmaceuticals), Adderall (Teva Pharmaceuticals), and Ritalin (Novartis).

Brain Volumes for Newborns Exposed to Opioids vs Unexposed Controls

The opioid-exposed group showed significantly smaller volumes in cortical gray matter (167.07 vs 176.35 cm³; difference, 9.28; 95% CI, 3.86-14.70; adjusted P = .002), deep gray matter (27.22 vs 28.76 cm³; difference, 1.54; 95% CI, 0.66-2.43; adjusted P = .002), white matter (159.90 vs 166.65 cm³; difference, 6.76; 95% CI, 1.71-11.81; adjusted P = .01), cerebellum (23.47 vs 24.99 cm³; difference, 1.52; 95% CI, 0.67-2.36; adjusted P = .002), brainstem (6.80 vs 7.18 cm³; difference, 0.38; 95% CI, 0.19-0.57; adjusted P = .001), left amygdala (0.48 vs 0.51 cm³; difference, 0.03; 95% CI, 0.004-0.05; adjusted P = .03), right amygdala (0.51 vs 0.55 cm³; difference, 0.04; 95% CI, 0.08-0.07; adjusted P = .002), and total brain (387.51 vs 407.06 cm³; difference, 19.55; 95% CI, 8.75-30.35; adjusted P = .002) compared with unexposed controls (Table 3). An analysis adjusting for head circumference at birth instead of birth weight was also performed with similar results (eTable 1 in Supplement 1). Brain volume differences between opioid-exposed and unexposed controls were not significantly different between males and female newborns (eTable 2 in Supplement 1).

Table 3. Brain Volumes of Opioid-Exposed Newborns and Unexposed Controls^a.

Brain region	Mean volume, cm³		Difference (95% CI)	Adjusted P value^b
Brain region	Opioid-exposed (n = 173)	Unexposed (n = 96)	Difference (95% CI)	Adjusted P value^b
Cortical gray matter	167.07	176.35	9.28 (3.86 to 14.70)	.002
White matter	159.90	166.65	6.76 (1.71 to 11.81)	.01
Deep gray matter	27.22	28.76	1.54 (0.66 to 2.43)	.002
Cerebellum	23.47	24.99	1.52 (0.67 to 2.36)	.002
Brainstem	6.80	7.18	0.38 (0.19 to 0.57)	.001
Left amygdala	0.48	0.51	0.03 (0.004 to 0.05)	.03
Right amygdala	0.51	0.55	0.04 (0.08 to 0.07)	.002
Left hippocampus	1.02	1.03	0.02 (−0.03 to 0.06)	.53
Right hippocampus	1.07	1.07	0.00 (−0.05 to 0.05)	.99
Total brain volume	387.51	407.06	19.55 (8.75 to 30.35)	.002

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^{^a}

Results of least-squares means from analysis of covariance, controlling for postmenstrual age at magnetic resonance imaging scan, sex, birth weight, maternal smoking status, and maternal education.

^{^b}

P values were adjusted for multiple testing based on the false discovery rate according to the Benjamini-Hochberg method. Adjusted P values <.05 were considered significant.

Brain Volumes for Newborns Exposed to Different Types of Opioids

Table 4 shows brain volumes for newborns exposed to methadone, buprenorphine, and other opioids and unexposed controls. Newborns exposed to either methadone or buprenorphine had significantly smaller volumes in cortical gray matter, deep gray matter, cerebellum, brainstem, and total brain compared to unexposed controls (all adjusted P < .05). Additionally, differences in white matter volume were significant only in methadone-exposed newborns (155.87 vs 166.64 cm³; adjusted P = .01), but not in those exposed to buprenorphine (160.51 vs 166.64 cm³; adjusted P = .12) and other opioids (163.18 vs 166.64 cm³; adjusted P = .67) compared to controls. Conversely, significant differences in right amygdala volume were observed only in buprenorphine-exposed newborns (0.50 vs 0.55 cm³; adjusted P = .008), but not in those exposed to methadone (0.51 vs 0.55 cm³; adjusted P = .16) and other opioids (0.52 vs 0.55 cm³; adjusted P = .38) compared to controls. Finally, newborns exposed to other opioids showed no significant differences compared to buprenorphine-exposed, methadone-exposed, or control newborns.

Table 4. Comparison of Brain Volumes of Infants Exposed to Different Opioid Types^a.

Brain region	Mean volume, cm³
Brain region	Methadone (n = 39)	Buprenorphine (n = 114)	Other opioids (n = 14)^b	Unexposed (n = 96)
Cortical gray matter	162.00^c	166.78^c	172.19	176.17
White matter	155.87^c	160.51	163.18	166.64
Deep gray matter	26.75^c	27.09^c	28.09	28.75
Cerebellum	23.05^c	23.30^c	23.73	24.92
Brainstem	6.79^c	6.77^c	6.82	7.17
Left amygdala	0.49	0.48	0.50	0.51
Right amygdala	0.51	0.50^c	0.52	0.55
Left hippocampus	1.02	1.00	1.07	1.03
Right hippocampus	1.068	1.06	1.11	1.07
Total brain volume	377.51^c	387.48^c	397.12	406.78

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^{^a}

Results of least-squares means from analysis of covariance, controlling for postmenstrual age at magnetic resonance imaging scan, sex, birth weight, maternal smoking status, and maternal education.

^{^b}

Other opioids include oxycodone, hydromorphone, morphine, fentanyl, hydrocodone, and heroin.

^{^c}

Different from unexposed controls (adjusted P < .05).

Brain Volume Differences in Newborns With Opioid-Only and Polysubstance Exposure Compared to Unexposed Controls

eTable 3 in Supplement 1 presents a subanalysis comparing brain volumes among newborns in the opioid-only exposure group, the opioid group with additional substance exposure (polysubstance group), and unexposed controls. Compared to controls, both the opioid-only and polysubstance exposure groups exhibited significant volume reductions in cortical gray matter (opioid-only: 168.10 vs 176.39 cm³; adjusted P = .04; polysubstance: 166.61 vs 176.39 cm³; adjusted P = .007), deep gray matter (opioid-only: 27.31 vs 28.77 cm³; adjusted P = .03; polysubstance: 27.18 vs 28.77 cm³; adjusted P = .007), cerebellum (opioid-only: 23.23 vs 24.98 cm³; adjusted P = .007; polysubstance: 23.58 vs 24.98 cm³; adjusted P = .01), brainstem (opioid-only: 6.75 vs 7.18 cm³; adjusted P = .005; polysubstance: 6.82 vs 7.18 cm³; adjusted P = .005), right amygdala (opioid-only: 0.50 vs 0.55 cm³; adjusted P = .01; polysubstance: 0.51 vs 0.55 cm³; adjusted P = .02), and total brain (opioid-only: 389.77 vs 407.15 cm³; adjusted P = .03; polysubstance: 386.49 vs 407.15 cm³; adjusted P = .005). Notably, the polysubstance exposure group also showed smaller volumes in white matter (159.27 vs 166.71 cm³; adjusted P = .02) and left amygdala (0.48 vs 0.51 cm³; adjusted P = .04) compared to controls, whereas no significant reductions in these 2 regions were found in the opioid-only exposure group. There were no significant differences in brain volumes between the opioid-only and polysubstance exposure groups.

Discussion

After adjusting for postmenstrual age at MRI, sex, birth weight, maternal smoking status, and maternal education, smaller brain volumes in multiple regions were found in a large cohort of 173 opioid-exposed newborns compared to 96 controls. In addition, this study’s large and diverse cohort enabled evaluation of the impact of different types of antenatal exposures on neonatal brain volumes. Although most regional brain volumes were smaller in newborns with antenatal exposure to either methadone or buprenorphine, methadone appeared to have an impact on white matter volume, while buprenorphine selectively affected right amygdala volume. Furthermore, polysubstance-exposed newborns showed smaller volumes in additional brain regions, including white matter and the left amygdala, compared to controls. These results are clinically relevant because brain volumes in infancy are associated with later neurodevelopmental outcomes in different populations, including preterm infants^17,18,19 and infants with congenital heart disease.^20,21 This study’s findings of impaired regional brain growth in newborns with antenatal opioid exposure may serve as early biomarkers of later neurodevelopmental dysfunction in this high-risk population.

Only 2 previous studies in human infants^11,12 have been published and reported smaller brain volumes in multiple regions following antenatal opioid exposure, corroborating the findings of this study. In a small observational study of 16 infants with antenatal exposure to methadone, buprenorphine, or other opioids,¹² whole brain volumes and basal ganglia were significantly smaller, and lateral ventricular volumes were larger than population means. However, this study did not include a control group and was unable to adjust for any potential confounders. A second prospective study of 29 infants with antenatal opioid exposure and 42 unexposed controls¹¹ found that exposed infants had smaller volumes of deep gray matter, bilateral thalamic ventrolateral nuclei, bilateral insular white matter, bilateral subthalamic nuclei, brainstem, and cerebrospinal fluids and larger volumes of the right cingulate gyrus white matter and left occipital lobe white matter. This study, although small, controlled for sex, postmenstrual age at scan, birth weight, and maternal education. However, it did not explore differences in type of opioid exposure. A study of 12 opioid-exposed fetuses (28-39 weeks’ gestation at MRI) and 16 unexposed fetuses (27-38 weeks’ gestation at MRI) found smaller cerebellar vermian dimension in opioid-exposed fetuses, although no macrostructural or maturational alterations were observed on brain MRI of the opioid-exposed fetuses.²² Another fetal MRI study found that opioid-exposed fetuses (mean [SD] of 32.2 [2.5] weeks’ gestation) had smaller cerebral frontooccipital diameter, biparietal diameter, corpus callosum length, vermis height, anteroposterior pons, and transverse cerebellar diameter, as well as a larger frontooccipital index, compared to unexposed fetuses.²³ Furthermore, a study on opioid-exposed neonates revealed sex-specific differences in inflammatory gene expression and higher expression in neonates with white matter hyperintensities compared to those without. These findings suggest that prenatal opioid exposure may contribute to both inflammation and white matter injury in the developing brain.²⁴ Taken together, these studies highlight the effects of prenatal opioid exposure on brain development, which appear to begin in utero.

Another major finding of this study is the differential effect of the type of antenatal opioid exposure on specific regions of the brain. Differences between neonatal outcomes after buprenorphine or methadone exposure have been described in the literature, including higher gestational age and birth weight²⁵ and fewer withdrawal symptoms²⁶ in newborns exposed to buprenorphine vs methadone. Differences in the mechanism of action between buprenorphine (a partial μ-opioid receptor agonist) and methadone (a full μ-opioid receptor agonist) may explain some of these findings in clinical outcomes and this study’s findings on brain volumes, but recent basic science literature may provide additional insight. Growth in human cortical organoids was significantly restricted with methadone treatment but not with buprenorphine treatment, possibly due to the κ-antagonist effect of buprenorphine.²⁷ In rats exposed to methadone or buprenorphine antenatally, the fetal brain concentration of methadone was twice that of the maternal brain, whereas the fetal brain concentration of buprenorphine was one-third of the maternal brain concentration.²⁸ A recent preclinical rat model exposed to antenatal methadone revealed lower brainwide functional connectivity and aberrant large-tract microstructural white matter tract integrity using in vivo diffusion tensor and functional MRI.²⁹ Using the same preclinical model, the authors previously reported a robust systemic inflammatory response syndrome and immune system dysfunction leading to immune cell priming and concomitant microstructural white matter injury.³⁰ This study’s findings of impaired white matter volumetric growth in exposed newborns are in keeping with these preclinical studies and suggest a particular vulnerability of the immature developing white matter exposed to antenatal methadone.

We also report that antenatal buprenorphine exposure is associated with regional-specific volumetric impairment of the amygdala. Antenatal exposure to buprenorphine alters interneuron migration and cortical network activity through the nociception opioid peptide (NOP) receptor in animal models^31,32 implicated in neurodevelopmental and psychiatric disorders. Notably, the NOP receptor is highly expressed in the cortex and limbic structures, including the amygdala.³¹ Altered amygdala growth in newborns has been implicated in the setting of prenatal maternal psychological distress.^33,34,35 The long-term functional implications of selective impairment of amygdala growth in this study’s cohort exposed to antenatal buprenorphine are unclear but may represent a neurobiological marker of later neuropsychiatric vulnerability.

The lack of differences found between newborns exposed to other opioids and controls could be due to the small sample size or the potentially intermittent opioid use for pain in the group using “other opioids.” These findings underscore the need for pregnant persons to have access to all options for treatment of opioid use disorder so they and their clinicians can evaluate the data and decide the best treatment option.

This subanalysis showed significant brain volume reductions in opioid-only and polysubstance-exposed newborns, with white matter and left amygdala volume reductions specific to the polysubstance group. These findings align with prior research showing that school-aged children with prenatal heroin and polysubstance exposure exhibited smaller total brain, cortical, and regional deep gray matter volumes, reduced cortical surface area, thinner cortex, and lower white matter fractional anisotropy compared to nonexposed peers.^36,37,38 Consistent with this study’s results, a study with 44 controls, 18 prenatal heroin-exposed, and 38 prenatal polysubstance-exposed youths demonstrated similar brain volumes in heroin- and polysubstance-exposed groups, with the latter showing more pronounced differences from controls, including reductions in total brain and deep gray matter volumes.³⁶ These observations suggest that the combined effects of multiple substances may synergistically disrupt neurodevelopment, leading to greater structural changes and contributing to long-term deficits in cognition, attention, and emotional regulation in offspring.^39,40,41 These findings emphasize the critical need to address the compounded risks of antenatal polysubstance exposure.

Limitations

This study has several limitations. The impact of the amount and duration of opioid exposure on neonatal brain volumes was not able to be evaluated due to the lack of detailed data. Maternal mental health disorders, which have been found to be previously associated with brain volume changes in the fetus and infant, were not controlled for. Finally, although we are prospectively collecting outcome data, the short- and longer-term impact of decreased brain volumes on later neurodevelopment in this cohort is not yet known.

Conclusions

In a large cohort of newborns with antenatal opioid exposure, significant reductions in global, regional, and tissue-specific brain volumes were identified compared to unexposed controls. These data suggest vulnerability of different regions of the brain to different opioids and polysubstance exposure. Serial neuroimaging and long-term neurobehavioral follow-up are underway to better understand the impact of antenatal opioid exposure on structure and function relationships and longer-term neurodevelopmental outcomes.

Supplement 1.

eFigure. Flow Diagram of Participants

eTable 1. Comparison of Brain Volumes of Opioid-Exposed Newborns to Unexposed Controls, Corrected for Head Circumference at Birth

eTable 2. Sex Differences in Brain Volumes Between Opioid-Exposed and Unexposed Groups

eTable 3. Comparison of Brain Volumes Among Newborns Exposed to Opioids Only, Newborns Exposed to Opioids Plus Additional Substances, and Unexposed Controls

jamapediatr-e250277-s001.pdf^{(645.8KB, pdf)}

Supplement 2.

Data Sharing Statement

jamapediatr-e250277-s002.pdf^{(16.3KB, pdf)}

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eFigure. Flow Diagram of Participants

eTable 1. Comparison of Brain Volumes of Opioid-Exposed Newborns to Unexposed Controls, Corrected for Head Circumference at Birth

eTable 2. Sex Differences in Brain Volumes Between Opioid-Exposed and Unexposed Groups

eTable 3. Comparison of Brain Volumes Among Newborns Exposed to Opioids Only, Newborns Exposed to Opioids Plus Additional Substances, and Unexposed Controls

jamapediatr-e250277-s001.pdf^{(645.8KB, pdf)}

Supplement 2.

Data Sharing Statement

jamapediatr-e250277-s002.pdf^{(16.3KB, pdf)}

[poi250008r1] 1.Ko JY, D’Angelo DV, Haight SC, et al. Vital signs: prescription opioid pain reliever use during pregnancy - 34 U.S. jurisdictions, 2019. MMWR Morb Mortal Wkly Rep. 2020;69(28):897-903. doi: 10.15585/mmwr.mm6928a1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r2] 2.Sanchez ES, Bigbee JW, Fobbs W, Robinson SE, Sato-Bigbee C. Opioid addiction and pregnancy: perinatal exposure to buprenorphine affects myelination in the developing brain. Glia. 2008;56(9):1017-1027. doi: 10.1002/glia.20675 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r3] 3.Vestal-Laborde AA, Eschenroeder AC, Bigbee JW, Robinson SE, Sato-Bigbee C. The opioid system and brain development: effects of methadone on the oligodendrocyte lineage and the early stages of myelination. Dev Neurosci. 2014;36(5):409-421. doi: 10.1159/000365074 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r4] 4.Wu CC, Hung CJ, Shen CH, et al. Prenatal buprenorphine exposure decreases neurogenesis in rats. Toxicol Lett. 2014;225(1):92-101. doi: 10.1016/j.toxlet.2013.12.001 [DOI] [PubMed] [Google Scholar]

[poi250008r5] 5.Madurai NK, Kitase Y, Hamimi S, et al. Methadone alters the peripheral inflammatory and central immune landscape following prenatal exposure in rats. Adv Drug Alcohol Res. 2022;2:10792. doi: 10.3389/adar.2022.10792 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r6] 6.Kim HM, Bone RM, McNeill B, Lee SJ, Gillon G, Woodward LJ. Preschool language development of children born to women with an opioid use disorder. Children (Basel). 2021;8(4):268. doi: 10.3390/children8040268 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r7] 7.Levine TA, Davie-Gray A, Kim HM, Lee SJ, Woodward LJ. Prenatal methadone exposure and child developmental outcomes in 2-year-old children. Dev Med Child Neurol. 2021;63(9):1114-1122. doi: 10.1111/dmcn.14808 [DOI] [PubMed] [Google Scholar]

[poi250008r8] 8.Schwartz AN, Reyes LM, Meschke LL, Kintziger KW. Prenatal opioid exposure and ADHD childhood symptoms: a meta-analysis. Children (Basel). 2021;8(2):106. doi: 10.3390/children8020106 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r9] 9.Hans SL, Jeremy RJ. Postneonatal mental and motor development of infants exposed in utero to opioid drugs. Infant Ment Health J. 2001;22(3):300-315. doi: 10.1002/imhj.1003 [DOI] [Google Scholar]

[poi250008r10] 10.Messinger DS, Bauer CR, Das A, et al. The maternal lifestyle study: cognitive, motor, and behavioral outcomes of cocaine-exposed and opiate-exposed infants through three years of age. Pediatrics. 2004;113(6):1677-1685. doi: 10.1542/peds.113.6.1677 [DOI] [PubMed] [Google Scholar]

[poi250008r11] 11.Merhar SL, Kline JE, Braimah A, et al. Prenatal opioid exposure is associated with smaller brain volumes in multiple regions. Pediatr Res. 2021;90(2):397-402. doi: 10.1038/s41390-020-01265-w [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r12] 12.Yuan Q, Rubic M, Seah J, et al. ; BOB (Brains, Opioids and Babies) Collaborative group . Do maternal opioids reduce neonatal regional brain volumes? a pilot study. J Perinatol. 2014;34(12):909-913. doi: 10.1038/jp.2014.111 [DOI] [PubMed] [Google Scholar]

[poi250008r13] 13.Bann CM, Newman JE, Poindexter B, et al. Outcomes of Babies with Opioid Exposure (OBOE): protocol of a prospective longitudinal cohort study. Pediatr Res. 2023;93(6):1772-1779. doi: 10.1038/s41390-022-02279-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r14] 14.Makropoulos A, Gousias IS, Ledig C, et al. Automatic whole brain MRI segmentation of the developing neonatal brain. IEEE Trans Med Imaging. 2014;33(9):1818-1831. doi: 10.1109/TMI.2014.2322280 [DOI] [PubMed] [Google Scholar]

[poi250008r15] 15.Zhao L, Asis-Cruz JD, Feng X, et al. Automated 3D fetal brain segmentation using an optimized deep learning approach. AJNR Am J Neuroradiol. 2022;43(3):448-454. doi: 10.3174/ajnr.A7419 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r16] 16.Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc Ser A Stat Soc. 1995;57(1):289-300. doi: 10.1111/j.2517-6161.1995.tb02031.x [DOI] [Google Scholar]

[poi250008r17] 17.Peterson BS, Anderson AW, Ehrenkranz R, et al. Regional brain volumes and their later neurodevelopmental correlates in term and preterm infants. Pediatrics. 2003;111(5 Pt 1):939-948. doi: 10.1542/peds.111.5.939 [DOI] [PubMed] [Google Scholar]

[poi250008r18] 18.Kline JE, Sita Priyanka Illapani V, He L, Parikh NA. Automated brain morphometric biomarkers from MRI at term predict motor development in very preterm infants. Neuroimage Clin. 2020;28:102475. doi: 10.1016/j.nicl.2020.102475 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r19] 19.Pagnozzi AM, van Eijk L, Pannek K, et al. Early brain morphometrics from neonatal MRI predict motor and cognitive outcomes at 2-years corrected age in very preterm infants. Neuroimage. 2023;267:119815. doi: 10.1016/j.neuroimage.2022.119815 [DOI] [PubMed] [Google Scholar]

[poi250008r20] 20.Meuwly E, Feldmann M, Knirsch W, et al. ; Research Group Heart and Brain* . Postoperative brain volumes are associated with one-year neurodevelopmental outcome in children with severe congenital heart disease. Sci Rep. 2019;9(1):10885. doi: 10.1038/s41598-019-47328-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r21] 21.Sadhwani A, Wypij D, Rofeberg V, et al. Fetal brain volume predicts neurodevelopment in congenital heart disease. Circulation. 2022;145(15):1108-1119. doi: 10.1161/CIRCULATIONAHA.121.056305 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r22] 22.Radhakrishnan R, Brown BP, Haas DM, Zang Y, Sparks C, Sadhasivam S. Pilot study of fetal brain development and morphometry in prenatal opioid exposure and smoking on fetal MRI. J Neuroradiol. 2022;49(1):53-58. doi: 10.1016/j.neurad.2020.12.004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r23] 23.Nagaraj UD, Kline-Fath BM, Zhang B, et al. MRI findings in third-trimester opioid-exposed fetuses, with focus on brain measurements: a prospective multicenter case-control study. AJR Am J Roentgenol. 2023;220(3):418-427. doi: 10.2214/AJR.22.28357 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi250008r24] 24.Yen E, Madan N, Tarui T, et al. Sex-specific inflammatory and white matter effects of prenatal opioid exposure: a pilot study. Pediatr Res. 2023;93(3):604-611. doi: 10.1038/s41390-022-02357-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Antenatal Opioid Exposure and Global and Regional Brain Volumes in Newborns

Yao Wu, PhD

Stephanie L Merhar, MD, MS

Carla M Bann, PhD

Jamie E Newman, PhD

Kushal Kapse, MS

Josepheen De Asis-Cruz, MD, PhD

Nicole Mack, MS

Sara B De Mauro, MD, MSCE

Namasivayam Ambalavanan, MD

Jonathan M Davis, MD

Scott A Lorch, MD, MSCE

Deanne Wilson-Costello, MD

Brenda B Poindexter, MD

Myriam Peralta-Carcelen, MD

Catherine Limperopoulos, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design

Demographics

Substance Use and Exposure

MRI Acquisition Protocol

Quantitative Volumetric MRI Analysis

Figure. Newborn Brain Segmentation on 3-Dimensional Magnetic Resonance Imaging.

Statistical Analysis

Results

Study Population

Table 1. Characteristics of the Study Cohort.

Medications Used During Pregnancy

Table 2. Self-Reported Maternal Medication Use During Pregnancy.

Brain Volumes for Newborns Exposed to Opioids vs Unexposed Controls

Table 3. Brain Volumes of Opioid-Exposed Newborns and Unexposed Controlsa.

Brain Volumes for Newborns Exposed to Different Types of Opioids

Table 4. Comparison of Brain Volumes of Infants Exposed to Different Opioid Typesa.

Brain Volume Differences in Newborns With Opioid-Only and Polysubstance Exposure Compared to Unexposed Controls

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Table 3. Brain Volumes of Opioid-Exposed Newborns and Unexposed Controls^a.

Table 4. Comparison of Brain Volumes of Infants Exposed to Different Opioid Types^a.