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Atypical Brain Development in Neonates Prenatally Exposed to Methadone

Presented at the Neonatal Society 2017 Summer Meeting.

Monnelly V1, Anblagan D2, Quigley A3, Cooper S5, Mactier H5, Semple S6, Bastin ME2, Boardman JP1,2

1 MRC Centre for Reproductive Health, University of Edinburgh
2 Centre for Clinical Brain Sciences, University of Edinburgh
3 Royal Hospital for Sick Children, Edinburgh
4 Royal Infirmary of Edinburgh
5 Princess Royal Maternity, Glasgow
6 Clinical Research Imaging Centre, University of Edinburgh

Background: Globally, 11 million people aged 15-64 use heroin and the prevalence is increasing in the 18-25 year age group (1). Maintenance methadone improves maternal and short-term neonatal outcomes for pregnant heroin users, and is commonly prescribed. Neonatal abstinence is a well recognised complication of maintenance methadone prescription and there are increasing reports of abnormal visual development among infants and children exposed prenatally to methadone and other substances (2,3). Diffusion MRI is sensitive detecting microstructural alteration in the developing brain (4,5). We tested the hypothesis that brain development is altered in neonates whose mothers have been prescribed maintenance methadone.

Methods: 20 methadone-exposed term neonates and 20 non-exposed term controls underwent diffusion MRI at a mean corrected age of 39+2 and 41+1 weeks, respectively. An optimised Tract-based Spatial Statistics (TBSS) pipeline (5) was used to perform voxel-wise statistical comparison of fractional anisotropy (FA) data. The MRI technique is sensitive to group wise differences using sample sizes of 20 per group (6). The study was funded by Theirworld (www.theirworld.org) and NRES approval was granted. All parents gave written, informed consent.

Results: Methadone exposed neonates had a similar GA at birth to the term control neonates (38+5 vs 39+1). Birthweight was lower in the methadone-exposed group (2721g vs 3349g) although only 2 of 20 neonates had a birth weight <3rd centile. Mean prescribed methadone dose at delivery was 69mg (range 8-160mg); 19 out of 20 women smoked tobacco and 12 of 20 used heroin during their pregnancy. Methadone-exposed neonates had decreased FA within the centrum semiovale, inferior longitudinal fasciculi (ILF), and the internal and external capsules after adjustment for GA at MRI (p < 0.05, corrected). Median FA across the white matter skeleton was 12% lower among methadone-exposed infants (see figure). Mean head circumference (HC) z-scores were lower in the methadone exposed group (- 0.52 (0.99) vs 1.15 (0.84), p < 0.001). After adjustment for HC z-scores, differences in FA remained in the anterior and posterior limbs of the internal capsule and the ILF.

Atypical Brain Development in Neonates Prenatally Exposed to Methadone

FA (y-axis) across the WM skeleton, grouped by methadone exposure

Conclusion: Prenatal methadone exposure is associated with microstructural alteration in major white matter tracts, independent of head growth. Further research to determine optimal management of opiate addiction during pregnancy should include evaluation of infant brain development and long-term neurocognitive outcome.

Corresponding author: j.boardman@ed.ac.uk

1. World Drug Report 2012. UNODC
2. Whitham JN et al Neurotoxicol Teratol, 2015
3. McGlone L et al Pediatrics, 2013
4. Boardman et al NeuroImage 2010
5. Ball G et al. NeuroImage 2010
6. Ball et al Plos One 2012

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