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Title: Prenatal methadone exposure and the developing brain
Author: Monnelly, Victoria J.
ISNI:       0000 0004 7969 1384
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Opioid use globally is increasing resulting in rising numbers of pregnant women exposing their unborn babies to opioid drugs, with an estimated 30,000 children each year in Europe born to mothers who have used opioids during pregnancy. Methadone is the recommended opioid substitute during pregnancy. Although maternal and perinatal outcomes for pregnant opioid users can be improved by maintenance methadone, there are increasing uncertainties about the safety of methadone on the developing brain and subsequent neurodevelopmental outcomes of children who are exposed prenatally to methadone. Advanced MRI techniques, such as diffusion MRI (dMRI), allow detailed non-invasive investigation of brain microstructure. Imaging biomarkers such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) derived from dMRI, are robust markers of white matter development, with FA associated with later neurodevelopmental outcome. Tract-based spatial statistics (TBSS) enables group-wise comparison of dMRI data and has been optimised for the neonatal brain. The aim of this thesis was to test the hypotheses that: (i) systematic review of existing published literature shows that prenatal methadone exposure is associated with altered neurodevelopment, visual development and / or brain tissue injury apparent on imaging; (ii) infants with prenatal methadone exposure have altered brain white matter microstructure when compared with term born unexposed control infants, which is manifest by a reduced FA and increased MD and increased RD; (iii) infants with prenatal methadone exposure have reduced total brain volumes and regional brain volumes when compared with term born unexposed infants. A systematic review of the literature was performed and where amenable data were pooled in random effects meta-analysis. 43 studies were included, 29 reported neurodevelopmental outcomes, 12 reported visual, and 2 reported neuroimaging data. 8 studies were meta-analysed and effect size was expressed as weighted mean difference (WMD) in developmental quotient scores. Childhood neurodevelopment, visual development and behaviour were altered in association with prenatal methadone exposure. Meta-analysis point estimates of cognitive indices (WMD of -4.43, 95% CI -7.24 to -1.63) and motor indices (PDI scores: WMD of -5.42, 95% CI -10.55 to -0.28) in 2 year old children exposed to prenatal methadone were lower than in age matched children with no prenatal drug exposure. Term born methadone-exposed infants were recruited and underwent an MRI scan shortly after birth. These were compared with 20 non-exposed term controls. An optimised Tract-based Spatial Statistics (TBSS) pipeline was used to perform voxel-wise statistical comparison of FA data. Prenatal methadone exposure was associated with microstructural alteration in major white matter tracts which were present at birth and when head circumference was adjusted for; these changes persisted in the anterior and posterior limbs of the internal capsule and the inferior longitudinal fasciculus (p < 0.05). In a subgroup of prenatal methadone exposed infants, lower white matter volumes (p = 0.049) and higher cerebrospinal fluid volumes (p = 0.001) were demonstrated when compared to healthy term control infants. This thesis has shown that through systematic review of the literature, there is an association between prenatal methadone exposure and both lower neurodevelopmental scores and visual dysfunction. TBSS showed that prenatal methadone exposure is associated with atypical white matter development compared with unexposed controls. Reduced FA in the white matter skeleton is apparent soon after birth, indicating an association between methadone exposure and brain development in utero; polydrug use among maternal cases limits causal inference. The data do not confirm the safety of methadone for medically assisted treatment of heroin addiction in pregnancy.
Supervisor: Boardman, James ; Bastin, Mark Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: methadone exposure ; diffusion MRI ; white matter tracts ; meta-analysis ; altered childhood development