Early breast milk exposure modifies brain connectivity in preterm infants.

Preterm infants are at increased risk of alterations in brain structure and connectivity, and subsequent neurocognitive impairment. Breast milk may be more advantageous than formula feed for promoting brain development in infants born at term, but uncertainties remain about its effect on preterm brain development and the optimal nutritional regimen for preterm infants. We test the hypothesis that breast milk exposure is associated with improved markers of brain development and connectivity in preterm infants at term equivalent age. We collected information about neonatal breast milk exposure and brain MRI at term equivalent age from 47 preterm infants (mean postmenstrual age [PMA] 29.43 weeks, range 23.28-33.0). Network-Based Statistics (NBS), Tract-based Spatial Statistics (TBSS) and volumetric analysis were used to investigate the effect of breast milk exposure on white matter water diffusion parameters, tissue volumes, and the structural connectome. Twenty-seven infants received exclusive breast milk feeds for ≥75% of days of in-patient care and this was associated with higher connectivity in the fractional anisotropy (FA)-weighted connectome compared with the group who had < 75% of days receiving exclusive breast milk feeds (NBS, p = 0.04). Within the TBSS white matter skeleton, the group that received ≥75% exclusive breast milk days exhibited higher FA within the corpus callosum, cingulum cingulate gyri, centrum semiovale, corticospinal tracts, arcuate fasciculi and posterior limbs of the internal capsule compared with the low exposure group after adjustment for PMA at birth, PMA at image acquisition, bronchopulmonary dysplasia, and chorioamnionitis (p < 0.05). The effect on structural connectivity and tract water diffusion parameters was greater with ≥90% exposure, suggesting a dose effect. There were no significant groupwise differences in brain volumes. Breast milk feeding in the weeks after preterm birth is associated with improved structural connectivity of developing networks and greater FA in major white matter fasciculi.

Improving data availability for brain image biobanking in healthy subjects: Practice-based suggestions from an international multidisciplinary working group.

Brain imaging is now ubiquitous in clinical practice and research. The case for bringing together large amounts of image data from well-characterised healthy subjects and those with a range of common brain diseases across the life course is now compelling. This report follows a meeting of international experts from multiple disciplines, all interested in brain image biobanking. The meeting included neuroimaging experts (clinical and non-clinical), computer scientists, epidemiologists, clinicians, ethicists, and lawyers involved in creating brain image banks. The meeting followed a structured format to discuss current and emerging brain image banks; applications such as atlases; conceptual and statistical problems (e.g. defining 'normality'); legal, ethical and technological issues (e.g. consents, potential for data linkage, data security, harmonisation, data storage and enabling of research data sharing). We summarise the lessons learned from the experiences of a wide range of individual image banks, and provide practical recommendations to enhance creation, use and reuse of neuroimaging data. Our aim is to maximise the benefit of the image data, provided voluntarily by research participants and funded by many organisations, for human health. Our ultimate vision is of a federated network of brain image biobanks accessible for large studies of brain structure and function.

Metric to quantify white matter damage on brain magnetic resonance images.

PURPOSE: Quantitative assessment of white matter hyperintensities (WMH) on structural Magnetic Resonance Imaging (MRI) is challenging. It is important to harmonise results from different software tools considering not only the volume but also the signal intensity. Here we propose and evaluate a metric of white matter (WM) damage that addresses this need. METHODS: We obtained WMH and normal-appearing white matter (NAWM) volumes from brain structural MRI from community dwelling older individuals and stroke patients enrolled in three different studies, using two automatic methods followed by manual editing by two to four observers blind to each other. We calculated the average intensity values on brain structural fluid-attenuation inversion recovery (FLAIR) MRI for the NAWM and WMH. The white matter damage metric is calculated as the proportion of WMH in brain tissue weighted by the relative image contrast of the WMH-to-NAWM. The new metric was evaluated using tissue microstructure parameters and visual ratings of small vessel disease burden and WMH: Fazekas score for WMH burden and Prins scale for WMH change. RESULTS: The correlation between the WM damage metric and the visual rating scores (Spearman ρ > =0.74, p < 0.0001) was slightly stronger than between the latter and WMH volumes (Spearman ρ > =0.72, p < 0.0001). The repeatability of the WM damage metric was better than WM volume (average median difference between measurements 3.26% (IQR 2.76%) and 5.88% (IQR 5.32%) respectively). The follow-up WM damage was highly related to total Prins score even when adjusted for baseline WM damage (ANCOVA, p < 0.0001), which was not always the case for WMH volume, as total Prins was highly associated with the change in the intense WMH volume (p = 0.0079, increase of 4.42 ml per unit change in total Prins, 95%CI [1.17 7.67]), but not with the change in less-intense, subtle WMH, which determined the volumetric change. CONCLUSION: The new metric is practical and simple to calculate. It is robust to variations in image processing methods and scanning protocols, and sensitive to subtle and severe white matter damage.

Contribution of white matter hyperintensities to ventricular enlargement in older adults.

Lateral ventricles might increase due to generalized tissue loss related to brain atrophy. Alternatively, they may expand into areas of tissue loss related to white matter hyperintensities (WMH). We assessed longitudinal associations between lateral ventricle and WMH volumes, accounting for total brain volume, blood pressure, history of stroke, cardiovascular disease, diabetes and smoking at ages 73, 76 and 79, in participants from the Lothian Birth Cohort 1936, including MRI data from all available time points. Lateral ventricle volume increased steadily with age, WMH volume change was more variable. WMH volume decreased in 20% and increased in remaining subjects. Over 6 years, lateral ventricle volume increased by 3% per year of age, 0.1% per mm Hg increase in blood pressure, 3.2% per 1% decrease of total brain volume, and 4.5% per 1% increase of WMH volume. Over time, lateral ventricle volumes were 19% smaller in women than men. Ventricular and WMH volume changes are modestly associated and independent of general brain atrophy, suggesting that their underlying processes do not fully overlap.

Prenatal methadone exposure is associated with altered neonatal brain development.

Methadone is used for medication-assisted treatment of heroin addiction during pregnancy. The neurodevelopmental outcome of children with prenatal methadone exposure can be sub-optimal. We tested the hypothesis that brain development is altered among newborn infants whose mothers were prescribed methadone. 20 methadone-exposed neonates born after 37 weeks' postmenstrual age (PMA) and 20 non-exposed controls underwent diffusion MRI at mean PMA of 39+ 2 and 41+ 1 weeks, respectively. An age-optimized Tract-based Spatial Statistics (TBSS) pipeline was used to perform voxel-wise statistical comparison of fractional anisotropy (FA) data between exposed and non-exposed neonates. 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, TFCE corrected). Median FA across the white matter skeleton was 12% lower among methadone-exposed infants. 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. Polydrug use among cases was common. Prenatal methadone exposure is associated with microstructural alteration in major white matter tracts, which is present at birth and is independent of head growth. Although the findings cannot be attributed to methadone per se, the data indicate that further research to determine optimal management of opioid use disorder during pregnancy is required. Future studies should evaluate childhood outcomes including infant brain development and long-term neurocognitive function.

Diffusion MRI parameters of corpus callosum and corticospinal tract in neonates: Comparison between region-of-interest and whole tract averaged measurements.

PURPOSE: Measures of white matter (WM) microstructure inferred from diffusion magnetic resonance imaging (dMRI) are useful for studying brain development. There is uncertainty about agreement between FA and MD values obtained from region-of-interest (ROI) versus whole tract approaches. We investigated agreement between dMRI measures using ROI and Probabilistic Neighbourhood Tractography (PNT) in genu of corpus callosum (gCC) and corticospinal tracts (CST). MATERIALS AND METHODS: 81 neonates underwent 64 direction DTI at term equivalent age. FA and MD values were extracted from a 8 mm3 ROI placed within the gCC, right and left posterior limbs of internal capsule. PNT was used to segment gCC and CSTs to calculate whole tract-averaged FA and MD. Agreement between values obtained by each method was compared using Bland-Altman statistics and Pearson's correlation. RESULTS: Across the 3 tracts the mean difference in FA measured by PNT and ROI ranged between 0.13 and 0.17, and the 95% limits of agreement did not include the possibility of no difference. For MD, the mean difference in values obtained from PNT and ROI ranged between 0.101 and 0.184 mm2/s × 10-3 mm2/s: the mean difference in gCC was 0.101 × 10-3 mm2/s with 95% limits of agreement that included the possibility of no difference, but there was significant disagreement in MD values measured in the CSTs. CONCLUSION: Agreement between dMRI measures of neonatal WM microstructure calculated from ROI and whole tract averaged methods is weak. ROI approaches may not provide sufficient representation of tract microstructure at the level of neural systems in newborns.

Machine learning of neuroimaging for assisted diagnosis of cognitive impairment and dementia: A systematic review.

INTRODUCTION: Advanced machine learning methods might help to identify dementia risk from neuroimaging, but their accuracy to date is unclear. METHODS: We systematically reviewed the literature, 2006 to late 2016, for machine learning studies differentiating healthy aging from dementia of various types, assessing study quality, and comparing accuracy at different disease boundaries. RESULTS: Of 111 relevant studies, most assessed Alzheimer's disease versus healthy controls, using AD Neuroimaging Initiative data, support vector machines, and only T1-weighted sequences. Accuracy was highest for differentiating Alzheimer's disease from healthy controls and poor for differentiating healthy controls versus mild cognitive impairment versus Alzheimer's disease or mild cognitive impairment converters versus nonconverters. Accuracy increased using combined data types, but not by data source, sample size, or machine learning method. DISCUSSION: Machine learning does not differentiate clinically relevant disease categories yet. More diverse data sets, combinations of different types of data, and close clinical integration of machine learning would help to advance the field.

Brain structural differences between 73- and 92-year olds matched for childhood intelligence, social background, and intracranial volume.

Fully characterizing age differences in the brain is a key task for combating aging-related cognitive decline. Using propensity score matching on 2 independent, narrow-age cohorts, we used data on childhood cognitive ability, socioeconomic background, and intracranial volume to match participants at mean age of 92 years (n = 42) to very similar participants at mean age of 73 years (n = 126). Examining a variety of global and regional structural neuroimaging variables, there were large differences in gray and white matter volumes, cortical surface area, cortical thickness, and white matter hyperintensity volume and spatial extent. In a mediation analysis, the total volume of white matter hyperintensities and total cortical surface area jointly mediated 24.9% of the relation between age and general cognitive ability (tissue volumes and cortical thickness were not significant mediators in this analysis). These findings provide an unusual and valuable perspective on neurostructural aging, in which brains from the 8th and 10th decades of life differ widely despite the same cognitive, socioeconomic, and brain-volumetric starting points.

Coupled changes in hippocampal structure and cognitive ability in later life.

Introduction: The hippocampus plays an important role in cognitive abilities which often decline with advancing age. Methods: In a longitudinal study of community-dwelling adults, we investigated whether there were coupled changes in hippocampal structure and verbal memory, working memory, and processing speed between the ages of 73 (N = 655) and 76 years (N = 469). Hippocampal structure was indexed by hippocampal volume, hippocampal volume as a percentage of intracranial volume (H_ICV), fractional anisotropy (FA), mean diffusivity (MD), and longitudinal relaxation time (T1). Results: Mean levels of hippocampal volume, H_ICV, FA, T1, and all three cognitive abilities domains decreased, whereas MD increased, from age 73 to 76. At baseline, higher hippocampal volume was associated with better working memory and verbal memory, but none of these correlations survived correction for multiple comparisons. Higher FA, lower MD, and lower T1 at baseline were associated with better cognitive abilities in all three domains; only the correlation between baseline hippocampal MD and T1, and change in the three cognitive domains, survived correction for multiple comparisons. Individuals with higher hippocampal MD at age 73 experienced a greater decline in all three cognitive abilities between ages 73 and 76. However, no significant associations with changes in cognitive abilities were found with hippocampal volume, FA, and T1 measures at baseline. Similarly, no significant associations were found between cognitive abilities at age 73 and changes in the hippocampal MRI biomarkers between ages 73 and 76. Conclusion: Our results provide evidence to better understand how the hippocampus ages in healthy adults in relation to the cognitive domains in which it is involved, suggesting that better hippocampal MD at age 73 predicts less relative decline in three important cognitive domains across the next 3 years. It can potentially assist in diagnosing early stages of aging-related neuropathologies, because in some cases, accelerated decline could predict pathologies.

Longitudinal serum S100ß and brain aging in the Lothian Birth Cohort 1936.

Elevated serum and cerebrospinal fluid concentrations of S100ß, a protein predominantly found in glia, are associated with intracranial injury and neurodegeneration, although concentrations are also influenced by several other factors. The longitudinal association between serum S100ß concentrations and brain health in nonpathological aging is unknown. In a large group (baseline N = 593; longitudinal N = 414) of community-dwelling older adults at ages 73 and 76 years, we examined cross-sectional and parallel longitudinal changes between serum S100ß and brain MRI parameters: white matter hyperintensities, perivascular space visibility, white matter fractional anisotropy and mean diffusivity (MD), global atrophy, and gray matter volume. Using bivariate change score structural equation models, correcting for age, sex, diabetes, and hypertension, higher S100ß was cross-sectionally associated with poorer general fractional anisotropy (r = -0.150, p = 0.001), which was strongest in the anterior thalamic (r = -0.155, p < 0.001) and cingulum bundles (r = -0.111, p = 0.005), and survived false discovery rate correction. Longitudinally, there were no significant associations between changes in brain imaging parameters and S100ß after false discovery rate correction. These data provide some weak evidence that S100ß may be an informative biomarker of brain white matter aging.

SEGMA: An Automatic SEGMentation Approach for Human Brain MRI Using Sliding Window and Random Forests.

Quantitative volumes from brain magnetic resonance imaging (MRI) acquired across the life course may be useful for investigating long term effects of risk and resilience factors for brain development and healthy aging, and for understanding early life determinants of adult brain structure. Therefore, there is an increasing need for automated segmentation tools that can be applied to images acquired at different life stages. We developed an automatic segmentation method for human brain MRI, where a sliding window approach and a multi-class random forest classifier were applied to high-dimensional feature vectors for accurate segmentation. The method performed well on brain MRI data acquired from 179 individuals, analyzed in three age groups: newborns (38-42 weeks gestational age), children and adolescents (4-17 years) and adults (35-71 years). As the method can learn from partially labeled datasets, it can be used to segment large-scale datasets efficiently. It could also be applied to different populations and imaging modalities across the life course.

Whole Brain Magnetic Resonance Image Atlases: A Systematic Review of Existing Atlases and Caveats for Use in Population Imaging.

Brain MRI atlases may be used to characterize brain structural changes across the life course. Atlases have important applications in research, e.g., as registration and segmentation targets to underpin image analysis in population imaging studies, and potentially in future in clinical practice, e.g., as templates for identifying brain structural changes out with normal limits, and increasingly for use in surgical planning. However, there are several caveats and limitations which must be considered before successfully applying brain MRI atlases to research and clinical problems. For example, the influential Talairach and Tournoux atlas was derived from a single fixed cadaveric brain from an elderly female with limited clinical information, yet is the basis of many modern atlases and is often used to report locations of functional activation. We systematically review currently available whole brain structural MRI atlases with particular reference to the implications for population imaging through to emerging clinical practice. We found 66 whole brain structural MRI atlases world-wide. The vast majority were based on T1, T2, and/or proton density (PD) structural sequences, had been derived using parametric statistics (inappropriate for brain volume distributions), had limited supporting clinical or cognitive data, and included few younger (>5 and <18 years) or older (>60 years) subjects. To successfully characterize brain structural features and their changes across different stages of life, we conclude that whole brain structural MRI atlases should include: more subjects at the upper and lower extremes of age; additional structural sequences, including fluid attenuation inversion recovery (FLAIR) and T2* sequences; a range of appropriate statistics, e.g., rank-based or non-parametric; and detailed cognitive and clinical profiles of the included subjects in order to increase the relevance and utility of these atlases.

A latent measure explains substantial variance in white matter microstructure across the newborn human brain.

A latent measure of white matter microstructure (g WM) provides a neural basis for information processing speed and intelligence in adults, but the temporal emergence of g WM during human development is unknown. We provide evidence that substantial variance in white matter microstructure is shared across a range of major tracts in the newborn brain. Based on diffusion MRI scans from 145 neonates [gestational age (GA) at birth range 23+2-41+5 weeks], the microstructural properties of eight major white matter tracts were calculated using probabilistic neighborhood tractography. Principal component analyses (PCAs) were carried out on the correlations between the eight tracts, separately for four tract-averaged water diffusion parameters: fractional anisotropy, and mean, radial and axial diffusivities. For all four parameters, PCAs revealed a single latent variable that explained around half of the variance across all eight tracts, and all tracts showed positive loadings. We considered the impact of early environment on general microstructural properties, by comparing term-born infants with preterm infants at term equivalent age. We found significant associations between GA at birth and the latent measure for each water diffusion measure; this effect was most apparent in projection and commissural fibers. These data show that a latent measure of white matter microstructure is present in very early life, well before myelination is widespread. Early exposure to extra-uterine life is associated with altered general properties of white matter microstructure, which could explain the high prevalence of cognitive impairment experienced by children born preterm.

Hippocampal morphology and cognitive functions in community-dwelling older people: the Lothian Birth Cohort 1936.

Structural measures of the hippocampus have been linked to a variety of memory processes and also to broader cognitive abilities. Gross volumetry has been widely used, yet the hippocampus has a complex formation, comprising distinct subfields which may be differentially sensitive to the deleterious effects of age, and to different aspects of cognitive performance. However, a comprehensive analysis of multidomain cognitive associations with hippocampal deformations among a large group of cognitively normal older adults is currently lacking. In 654 participants of the Lothian Birth Cohort 1936 (mean age = 72.5, SD = 0.71 years), we examined associations between the morphology of the hippocampus and a variety of memory tests (spatial span, letter-number sequencing, verbal recall, and digit backwards), as well as broader cognitive domains (latent measures of speed, fluid intelligence, and memory). Following correction for age, sex, and vascular risk factors, analysis of memory subtests revealed that only right hippocampal associations in relation to spatial memory survived type 1 error correction in subiculum and in CA1 at the head (ß = 0.201, p = 5.843 × 10-4, outward), and in the ventral tail section of CA1 (ß = -0.272, p = 1.347 × 10-5, inward). With respect to latent measures of cognitive domains, only deformations associated with processing speed survived type 1 error correction in bilateral subiculum (ßabsolute ≤ 0.247, p < 1.369 × 10-4, outward), bilaterally in the ventral tail section of CA1 (ßabsolute ≤ 0.242, p < 3.451 × 10-6, inward), and a cluster at the left anterior-to-dorsal region of the head (ß = 0.199, p = 5.220 × 10-6, outward). Overall, our results indicate that a complex pattern of both inward and outward hippocampal deformations are associated with better processing speed and spatial memory in older age, suggesting that complex shape-based hippocampal analyses may provide valuable information beyond gross volumetry.

Associations between hippocampal morphology, diffusion characteristics, and salivary cortisol in older men.

High, unabated glucocorticoid (GC) levels are thought to selectively damage certain tissue types. The hippocampus is thought to be particularly susceptible to such effects, and though findings from animal models and human patients provide some support for this hypothesis, evidence for associations between elevated GCs and lower hippocampal volumes in older age (when GC levels are at greater risk of dysregulation) is inconclusive. To address the possibility that the effects of GCs in non-pathological ageing may be too subtle for gross volumetry to reliably detect, we analyse associations between salivary cortisol (diurnal and reactive measures), hippocampal morphology and diffusion characteristics in 88 males, aged ∼73 years. However, our results provide only weak support for this hypothesis. Though nominally significant peaks in morphology were found in both hippocampi across all salivary cortisol measures (standardised ß magnitudes<0.518, puncorrected>0.0000003), associations were both positive and negative, and none survived false discovery rate correction. We found one single significant association (out of 12 comparisons) between a general measure of hippocampal diffusion and reactive cortisol slope (ß=0.290, p=0.008) which appeared to be driven predominantly by mean diffusivity but did not survive correction for multiple testing. The current data therefore do not clearly support the hypothesis that elevated cortisol levels are associated with subtle variations in hippocampal shape or microstructure in non-pathological older age.

Parcellation of the Healthy Neonatal Brain into 107 Regions Using Atlas Propagation through Intermediate Time Points in Childhood.

Neuroimage analysis pipelines rely on parcellated atlases generated from healthy individuals to provide anatomic context to structural and diffusion MRI data. Atlases constructed using adult data introduce bias into studies of early brain development. We aimed to create a neonatal brain atlas of healthy subjects that can be applied to multi-modal MRI data. Structural and diffusion 3T MRI scans were acquired soon after birth from 33 typically developing neonates born at term (mean postmenstrual age at birth 39(+5) weeks, range 37(+2)-41(+6)). An adult brain atlas (SRI24/TZO) was propagated to the neonatal data using temporal registration via childhood templates with dense temporal samples (NIH Pediatric Database), with the final atlas (Edinburgh Neonatal Atlas, ENA33) constructed using the Symmetric Group Normalization (SyGN) method. After this step, the computed final transformations were applied to T2-weighted data, and fractional anisotropy, mean diffusivity, and tissue segmentations to provide a multi-modal atlas with 107 anatomical regions; a symmetric version was also created to facilitate studies of laterality. Volumes of each region of interest were measured to provide reference data from normal subjects. Because this atlas is generated from step-wise propagation of adult labels through intermediate time points in childhood, it may serve as a useful starting point for modeling brain growth during development.

Association between preterm brain injury and exposure to chorioamnionitis during fetal life.

Preterm infants are susceptible to inflammation-induced white matter injury but the exposures that lead to this are uncertain. Histologic chorioamnionitis (HCA) reflects intrauterine inflammation, can trigger a fetal inflammatory response, and is closely associated with premature birth. In a cohort of 90 preterm infants with detailed placental histology and neonatal brain magnetic resonance imaging (MRI) data at term equivalent age, we used Tract-based Spatial Statistics (TBSS) to perform voxel-wise statistical comparison of fractional anisotropy (FA) data and computational morphometry analysis to compute the volumes of whole brain, tissue compartments and cerebrospinal fluid, to test the hypothesis that HCA is an independent antenatal risk factor for preterm brain injury. Twenty-six (29%) infants had HCA and this was associated with decreased FA in the genu, cingulum cingulate gyri, centrum semiovale, inferior longitudinal fasciculi, limbs of the internal capsule, external capsule and cerebellum (p < 0.05, corrected), independent of degree of prematurity, bronchopulmonary dysplasia and postnatal sepsis. This suggests that diffuse white matter injury begins in utero for a significant proportion of preterm infants, which focuses attention on the development of methods for detecting fetuses and placentas at risk as a means of reducing preterm brain injury.

Tract shape modeling detects changes associated with preterm birth and neuroprotective treatment effects.

Preterm birth is associated with altered connectivity of neural circuits. We developed a tract segmentation method that provides measures of tract shape and integrity (probabilistic neighborhood tractography, PNT) from diffusion MRI (dMRI) data to test the hypotheses: 1) preterm birth is associated with alterations in tract topology (R), and tract-averaged mean diffusivity (〈D〉) and fractional anisotropy (FA); 2) neural systems are separable based on tract-averaged dMRI parameters; and 3) PNT can detect neuroprotective treatment effects. dMRI data were collected from 87 preterm infants (mean gestational age 29(+1) weeks, range 23(+2) -34(+6)) at term equivalent age and 24 controls (mean gestational age 39(+6) weeks). PNT was used to segment eight major fasciculi, characterize topology, and extract tract-averaged〈D〉and FA. Tract topology was altered by preterm birth in all tracts except the splenium (p < 0.05, false discovery rate [FDR] corrected). After adjustment for age at scan, tract-averaged〈D〉was increased in the genu and splenium, right corticospinal tract (CST) and the left and right inferior longitudinal fasciculi (ILF) in preterm infants compared with controls (p < 0.05, FDR), while tract-averaged FA was decreased in the splenium and left ILF (p < 0.05, FDR). Specific fasciculi were separable based on tract-averaged〈D〉and FA values. There was a modest decrease in tract-averaged〈D〉in the splenium of preterm infants who had been exposed to antenatal MgSO4 for neuroprotection (p = 0.002). Tract topology is a biomarker of preterm brain injury. The data provide proof of concept that tract-averaged dMRI parameters have utility for evaluating tissue effects of perinatal neuroprotective strategies.

Maternal smoking during pregnancy and fetal organ growth: a magnetic resonance imaging study.

OBJECTIVE: To study whether maternal cigarette smoking during pregnancy is associated with alterations in the growth of fetal lungs, kidneys, liver, brain, and placenta. DESIGN: A case-control study, with operators performing the image analysis blinded. SETTING: Study performed on a research-dedicated magnetic resonance imaging (MRI) scanner (1.5 T) with participants recruited from a large teaching hospital in the United Kingdom. PARTICIPANTS: A total of 26 pregnant women (13 current smokers, 13 non smokers) were recruited; 18 women (10 current smokers, 8 nonsmokers) returned for the second scan later in their pregnancy. METHODS: Each fetus was scanned with MRI at 22-27 weeks and 33-38 weeks gestational age (GA). MAIN OUTCOME MEASURES: Images obtained with MRI were used to measure volumes of the fetal brain, kidneys, lungs, liver and overall fetal size, as well as placental volumes. RESULTS: Exposed fetuses showed lower brain volumes, kidney volumes, and total fetal volumes, with this effect being greater at visit 2 than at visit 1 for brain and kidney volumes, and greater at visit 1 than at visit 2 for total fetal volume. Exposed fetuses also demonstrated lower lung volume and placental volume, and this effect was similar at both visits. No difference was found between the exposed and nonexposed fetuses with regards to liver volume. CONCLUSION: Magnetic resonance imaging has been used to show that maternal smoking is associated with reduced growth of fetal brain, lung and kidney; this effect persists even when the volumes are corrected for maternal education, gestational age, and fetal sex. As expected, the fetuses exposed to maternal smoking are smaller in size. Similarly, placental volumes are smaller in smoking versus nonsmoking pregnant women.