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Prenatal opioid exposure is associated with delayed locomotor performance at multiple stages of early child development1,2 and with smaller neuroanatomical structures, such as the basal ganglia.3 The motor cortex, which controls speech and motor skills, may also be vulnerable to drug exposure, but to our knowledge, this has yet to be assessed. Identifying risks of exposure associated with brain structures is critical for prevention and intervention strategies for cognitive effects that can last long after conception.3,4
Most neuroanatomical opioid-related research has focused on heroin, used smaller samples, and failed to control for social factors that are associated with development. Using data from the Adolescent Brain Cognitive Development (ABCD) study,5 we aimed to identify structural differences of the precentral gyrus (motor cortex) among children with reported prenatal opioid exposure compared with children with no reported exposure, controlling for present social factors.
Using magnetic resonance imaging, we compared cortical volumes, cortical areas, and thicknesses of the precentral gyrus between children prenatally exposed to opioids and nonexposed children. The data were collected through the ABCD study, which also includes developmental questionnaires, reports of parents’ and children’s medical histories, and current sociodemographic information. Parent-reported (or guardian-reported) prenatal opioid exposure was classified as a binary indicator through standardized survey questions about the biological mothers’ prescription medication and drug usage during pregnancy (n = 11 530). Mean differences in the cortical volumes, cortical areas, and thicknesses of the precentral gyri, using Destrieux parcellations from the ABCD study,6 were assessed between groups using appropriate weightings and were calculated with appropriate weighting and statistically tested using multilevel, bivariate regression analyses, with the level of significance set at a 2-tailed P value less than .05. Written informed consent from guardians and written assent from children were collected at study sites, under single institutional review board approval from the University of California, San Diego. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Multivariable regression models controlled for maternal tobacco and alcohol use after learning of pregnancy and current sociodemographic factors (financial risk, race/ethnicity, sex, and single-adult household). Sample size was reduced (6%) for this analysis (n = 10 840) due to missing data. Statistical analyses were performed applying the ABCD sampling design, clustering siblings/twins within families and by study site, with bootstrapping, using Stata software version 14.2 (StataCorp).
Of the 11 530 child participants, 6042.87 (52.4%; 95% CI, 51.4-53.4) were male, and the mean (SD) age was 9.91 (0.63) years. The sample included 6030 children (52.4%; 95% CI, 51.4-53.3) who were white, 2344 (20.4%; 95% CI, 19.7-21.1) who were Hispanic, and 1702 (14.8%; 95% CI, 14.1-15.5) who were black, which was not statistically different between those with and without prenatal opioid exposure (adjusted χ2 = 1.94; P = .10). After assessing maternal medication and drug use during pregnancy, 150 children were identified as having prenatal prescription opioid exposure with 144 having magnetic resonance imaging scans. The mean (SE) cortical volume of the left precentral gyrus was smaller among children with prenatal opioid exposure compared with those without (7329.02 [88.51] mm3 vs 7566.00 [9.85] mm3; difference, 236.98 [89.82] mm3; Cohen d = 0.223) (Table 1). Similarly, the mean (SE) volume of the right precentral gyrus was smaller among those with prenatal opioid exposure compared with those without (7195.65 [88.32] mm3 vs 7481.74 [9.50] mm3; difference, 286.09 [85.84] mm3; Cohen d = 0.271). The surface areas of the precentral gyri were also smaller among children exposed to prescription opioids (Table 1). Total cortical area and volume and thickness of the precentral gyrus were not statistically significantly different between groups. The differences in cortical volumes and cortical areas of gyri remained statistically significant when controlling for sociodemographic factors in the regression models (Table 2) as well prenatal alcohol and tobacco exposures, which were also statistically significant.
To our knowledge, this article is among the first to find an association of prenatal prescription opioid exposure with neuroanatomical differences in the brains of children. Analysis of other variables within the ABCD study data set may elucidate the functional, cognitive, and behavioral results of these neuroanatomical differences and may inform future therapeutic models for improving outcomes for these children. With the longitudinal ABCD study, researchers may explore whether these structural differences persist over time.
Future research may investigate whether medications for the treatment of opioid use disorder, like buprenorphine and methadone, result in similar brain changes and assess whether opioid exposure has a dose-dependent effect on gyri size, which was a limitation of our study. In summary, these results suggest a need for clinical screening for prenatal opioid exposure during pregnancy and during the life span as well as reevaluation of risks and benefits of prescription opioids during pregnancy.
Accepted for Publication: January 9, 2020.
Corresponding Author: Micah L. Hartwell, PhD, Department of Psychiatry and Behavioral Science, Oklahoma State University Center for Health Sciences, 1111 W 17th St, Tulsa, OK 74107 (email@example.com).
Published Online: June 8, 2020. doi:10.1001/jamapediatrics.2020.0937
Author Contributions: Dr Hartwell had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Hartwell, Croff, Breslin.
Acquisition, analysis, or interpretation of data: Hartwell, Morris, Breslin, Dunn.
Drafting of the manuscript: Hartwell, Morris.
Critical revision of the manuscript for important intellectual content: Croff, Breslin, Dunn.
Statistical analysis: Hartwell.
Obtained funding: Morris.
Administrative, technical, or material support: Croff, Dunn.
Study supervision: Croff, Morris, Breslin.
Conflict of Interest Disclosures: Dr Croff has received grants from the National Institutes of Health, Substance Abuse and Mental Health Services Administration, and Health Resources and Services Administration outside the submitted work. Dr Morris and Ms Breslin have received grants from Laureate Institute for Brain Research during the conduct of the study. No other disclosures were reported.
Funding/Support: Dr Morris and Ms Breslin are funded by grant U01DA041089 from the National Institutes of Health to the Laureate Institute for Brain Research. The Adolescent Brain Cognitive Development study is supported by the National Institutes of Health and additional federal partners under grants U01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, and U24DA041147. Drs Croff and Morris were also supported by Institutional Development Award P20GM109097 from the National Institute of General Medical Sciences and grant 1R34DA050343 from the National Institute on Drug Abuse.
Role of the Funder/Sponsor: The National Institute on Drug Abuse was involved in the design and conduct of the study and management of the data. The funders otherwise had no role in the collection, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: This article reflects the views of the authors and may not reflect the opinions or views of the National Institutes of Health or Adolescent Brain Cognitive Development Consortium Investigators.
Additional Information: Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive Development study (https://abcdstudy.org), held in the National Institute of Mental Health Data Archive. This is a multisite, longitudinal study designed to recruit more than 10 000 children aged 9 to 10 years and follow up with them over 10 years into early adulthood. The Adolescent Brain Cognitive Development data repository grows and changes over time. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/wp-content/uploads/2019/04/Consortium_Members.pdf. The Adolescent Brain Cognitive Development data used in this report came from the National Institute of Mental Health Data Archive (doi:10.15154/1412097).
Hartwell ML, Croff JM, Morris AS, Breslin FJ, Dunn K. Association of Prenatal Opioid Exposure With Precentral Gyrus Volume in Children. JAMA Pediatr. 2020;174(9):893–896. doi:10.1001/jamapediatrics.2020.0937
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