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
