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The aim of this study was to investigate the effect of serial amnioinfusion therapy (SAT) for pulmonary hypoplasia in lower urinary tract obstruction (LUTO) or congenital renal anomalies (CRAs), introduce patient selection criteria, and present a case of SAT in bilateral renal agenesis. We conducted a search of the MEDLINE, EMBASE, Web of Science, and Scopus databases for articles published from database inception to November 10, 2017. Eight studies with 17 patients (7 LUTO, 8 CRA, and 2 LUTO + CRA) were included in the study. The median age of the mothers was 31 years (N=9; interquartile range [IQR], 29-33.5 years), the number of amnioinfusions was 7 (N=17; IQR, 4.5-21), gestational age at first amnioinfusion was 23 weeks and 4 days (N=17; IQR, 21-24.07), gestational age at delivery was 32 weeks and 2 days (N=17; IQR, 30 weeks to 35 weeks and 6.5 days), birthweight of newborns was 3.7 kg (N= 9; IQR, 2.7-3.7 kg), Apgar score at 1 minute was 2.5 (N=8; IQR, 1-6.5), and Apgar score at 5 minutes was 5.5 (N=8; IQR, 0-7.75). In conclusion, SAT may provide fetal pulmonary palliation by reducing the risk of newborn pulmonary compromise secondary to oligohydramnios. Multidisciplinary research efforts are required to further inform treatment and counseling guidelines. We propose a multidisciplinary approach to prenatal classification of fetuses with LUTO to inform patient selection.

Highlights • Estrogen receptor or progesterone receptor positivity are unusual in cervical adenocarcinomas. • Estrogen receptor positivity in pregnancy could be associated with a faster growth rate. • Both patients presented remain free of recurrence after definitive treatment., The incidence of adenocarcinoma of the cervix in pregnancy is exceptionally rare, and thus there is no consensus on its management. Here, we report two cases of adenocarcinoma of the cervix diagnosed in the context of pregnancy. In our first case, a patient referred to colposcopy for atypical glandular cells of undetermined significance was subsequently diagnosed with well differentiated endocervical adenocarcinoma on cone biopsy. Just prior to the cone biopsy, she was incidentally found to have a first trimester pregnancy loss. The patient subsequently underwent a radical hysterectomy and bilateral sentinel lymph node dissection. Final pathology revealed a stage 1B1 (FIGO 2009) well differentiated adenocarcinoma of the cervix. Interestingly, the tumour was positive for estrogen receptor, which is unusual for cervical adenocarcinoma. In our second case, a patient presented with a pedunculated, exophytic cervical neoplasm at 31 weeks GA with self-limiting antepartum hemorrhage. The primary lesion measured 52 mm in diameter on MRI and was amputated at the base during the patient’s elective repeat cesarean section. Final pathology revealed a stage IB2 (FIGO 2009) mucinous adenocarcinoma of the cervix. The patient subsequently underwent a radical hysterectomy and bilateral pelvic lymph node dissection 17 weeks after initial presentation. The depth of invasion was 2.2 mm, restricted to the inner third of the cervical wall, and there was no lymphovascular space invasion in the surgical specimen. Surgical margins, parametria, and lymph nodes were all negative for adenocarcinoma. This tumour was also found to be estrogen receptor/progesterone receptor (ER/PR) positive, again unusual for cervical adenocarcinoma. P16 was strongly positive and HPV DNA studies were also positive for human papilloma virus 18. The patient received adjuvant external beam radiotherapy to the pelvis and currently remains in remission.

Background Binary prediction-models for outcome [death, cognition, presence and severity of cerebral palsy (CP)], using MRI and early clinical data applicable for individual outcome prediction have not been developed. Methods From Dec 1st 2006 until Dec 31st 2013, we recruited 178 infants into a population-based cohort with moderate or severe hypoxic-ischaemic encephalopathy (HIE) including postnatal collapse (PNC, n = 12) and additional diagnoses (n = 12) using CoolCap/TOBY-trial entry-criteria including depressed amplitude-integrated EEG (aEEG). Early clinical/biochemical variables and MRI scans (median day 8) were obtained in 168 infants. Injury severity was scored for cortex, basal ganglia/thalami (BGT), white matter (WM) and posterior limb of the internal capsule, summating to a total injury score (TIS, range 0–11). Outcome was categorized as adverse or favourable at 18–24 months from Bayley-III domains (cut-off 85) and neurological examination including CP classification. • View related content for this article Findings HIE and entry-aEEG severity were stable throughout the study. Outcome was favourable in 133/178 infants and adverse in 45/178: 17 died, 28 had low Cognition/Language scores, (including 9 with severe CP and 6 mild); seven had mild CP with favourable cognitive outcome. WMxBGT product scores and TIS were strong outcome predictors, and prediction improved when clinical/biochemical variables were added in binary logistic regression. The Positive Predictive Value for adverse outcome was 88%, increasing to 95% after excluding infants with PNC and additional diagnoses. Using WMxBGT in the regression predicted 8 of the 9 children with severe CP. Interpretation Binary logistic regression with WMxBGT or TIS and clinical variables gave excellent outcome prediction being 12% better than single variable cross-tabulation. Our MRI scoring and regression models are readily accessible and deserve investigation in other cohorts for group and individual prediction. Funding We thank the National Health Service (NHS) and our Universities and funders in UK and Norway: SPARKS, The Moulton Foundation, The Norwegian Research Council, The Lærdal Foundation for Acute Medicine and charitable donations for their support for cooling therapy.

Background There are few reports of miscarriages or stillbirths in women infected with SARS-CoV-2. We present five consecutive cases of fetal death (≥12 weeks) without other putative causes in women with laboratory-confirmed (RT-PCR) COVID-19 managed in a single Brazilian institution. Case series All five women were outpatients with mild or moderate forms of COVID-19 and were not taking any medication. Four were nulliparous, all were overweight or obese, and none had any comorbidities or pregnancy complications that could contribute to fetal demise. Fetal death occurred at 21–38 weeks of gestation, on COVID-days 1–22. SARS-Cov-2 was detected by RT-PCR in amniotic fluid in one case and in placental specimens in two cases. All five women had acute chorioamnionitis on placental histology, massive deposition of fibrin, mixed intervillitis/villitis, and intense neutrophil and lymphocyte infiltration. One fetus had neutrophils inside alveolar spaces, suggestive of fetal infection. Conclusions These five cases of fetal demise in women with confirmed COVID-19 without any other significant clinical or obstetric disorders suggest that fetal death can be an outcome of SARS-CoV-2 infection in pregnancy. The intense placental inflammatory reaction in all five cases raises the possibility of a direct effect of SARS-CoV-2 on the placenta., Highlights • There are few reports of stillbirth in women with COVID-19. • We describe 5 fetal deaths at 21–38 weeks of gestation. • All had acute chorioamnionitis on placental histology. • SARS-CoV-2 was detected in the amniotic fluid in one case and in the placenta in two cases. • SARS-CoV-2 may produce placental infection.

Human cortical development during the third trimester is characterised by macro- and microstructural changes which are reflected in alterations in diffusion MRI (dMRI) measures, with significant decreases in cortical mean diffusivity (MD) and fractional anisotropy (FA). This has been interpreted as reflecting increased cellular density and dendritic arborisation. However, the fall in FA stops abruptly at 38 weeks post-menstrual age (PMA), and then tends to plateau, while MD continues to fall, suggesting a more complex picture and raising the hypothesis that after this age development is dominated by continuing increase in neural and organelle density rather than alterations in the geometry of dendritic trees. To test this, we used neurite orientation dispersion and density imaging (NODDI), acquiring multi-shell, high angular resolution dMRI and measures of cortical volume and mean curvature in 99 preterm infants scanned between 25 and 47 weeks PMA. We predicted that increased neurite and organelle density would be reflected in increases in neurite density index (NDI), while a relatively unchanging geometrical structure would be associated with constant orientation dispersion index (ODI). As dendritic arborisation is likely to be one of the drivers of gyrification, we also predicted that measures of cortical volume and curvature would correlate with ODI and show slower growth after 38 weeks. We observed a decrease of MD throughout the period, while cortical FA decreased from 25 to 38 weeks PMA and then increased. ODI increased up to 38 weeks and then plateaued, while NDI rose after 38 weeks. The evolution of ODI correlated with cortical volume and curvature. Regional analysis of cortical microstructure revealed a heterogenous pattern with increases in FA and NDI after 38 weeks confined to primary motor and sensory regions. These results support the interpretation that cortical development between 25 and 38 weeks PMA shows a predominant increase in dendritic arborisation and neurite growth, while between 38 and 47 weeks PMA it is dominated by increasing cellular and organelle density., Graphical abstract Image 1, Highlights • DTI and NODDI cortical measures between 25 and 47 weeks GA • Early cortical changes consistent with dendritic arborisation and neurite growth • After 38 weeks cortical changes consistent with increasing cellular density • Cortical curvature evolves in parallel with dendritic arborisation

Highlights • Preterm infant white matter tracts uniquely predict later toddler language. • Neonatal medical history moderates posterior corpus callosum–language relations. • Different associations by tract may relate to brain maturation and medical history., Aim To determine whether variability in diffusion MRI (dMRI) white matter tract metrics, obtained in a cohort of preterm infants prior to neonatal hospital discharge, would be associated with language outcomes at age 2 years, after consideration of age at scan and number of major neonatal complications. Method 30 children, gestational age 28.9 (2.4) weeks, underwent dMRI at mean post menstrual age 36.4 (1.4) weeks and language assessment with the Bayley Scales of Infant Development–III at mean age 22.2 (1.7) months chronological age. Mean fractional anisotropy (FA) and mean diffusivity (MD) were calculated for 5 white matter tracts. Hierarchical linear regression assessed associations between tract FA, moderating variables, and language outcomes. Results FA of the left inferior longitudinal fasciculus accounted for 17% (p = 0.03) of the variance in composite language and FA of the posterior corpus callosum accounted for 19% (p = 0.02) of the variance in composite language, beyond that accounted for by post-menstrual age at scan and neonatal medical complications. The number of neonatal medical complications moderated the relationship between language and posterior corpus callosum FA but did not moderate the association in the other tract. Conclusion Language at age 2 is associated with white matter metrics in early infancy in preterm children. The different pattern of associations by fiber group may relate to the stage of brain maturation and/or the nature and timing of medical complications related to preterm birth. Future studies should replicate these findings with a larger sample size to assure reliability of the findings.

Background Children exposed to gestational diabetes mellitus (GDM) in utero are at increased risk of neurodevelopmental difficulties, including autism and impaired motor control. However, the underlying neurophysiology is unknown. Methods Using transcranial magnetic stimulation, we assessed cortical excitability, long-term depression (LTD)-like neuroplasticity in 45 GDM-exposed and 12 control children aged 11–13 years. Data were analysed against salivary cortisol and maternal diabetes severity and treatment (insulin [N = 22] or metformin [N = 23]) during pregnancy. Findings GDM-exposed children had reduced cortical excitability (p = .003), LTD-like neuroplasticity (p = .005), and salivary cortisol (p, Highlights • Children exposed to gestational diabetes (GDM) had lower cortical excitability, measured as higher resting motor thresholds. • The GDM group also exhibited smaller LTD-like neuroplastic responses to repetitive brain stimulation. • These were associated with lower salivary cortisol and with maternal diabetes severity, especially insulin resistance. Our results suggest that gestational diabetes, even when detected and treated as per clinical guidelines, has subtle effects on important neurophysiological processes persisting into early adolescence, including neuroplasticity and possibly cortisol secretion. The extent of these effects is related to the severity of maternal diabetes, particularly insulin resistance, during mid pregnancy. These results may aid in understanding how insulin resistance and hyperglycemia affect the developing brain. Further, our results indicate that earlier detection and pharmacologic treatment of gestational diabetes may attenuate or prevent these changes to neurodevelopment, and that maternal metformin treatment does not influence these aspects of development.

Background Preterm infants are at high risk of diffuse white matter injury and adverse neurodevelopmental outcome. The multiple hit hypothesis suggests that the risk of white matter injury increases with cumulative exposure to multiple perinatal risk factors. Our aim was to test this hypothesis in a large cohort of preterm infants using diffusion weighted magnetic resonance imaging (dMRI). Methods We studied 491 infants (52% male) without focal destructive brain lesions born at, Highlights • White matter injury was assessed in 491 preterm infants at term equivalent age. • Aberrant white matter development was associated with several perinatal factors. • Our findings support the multiple hit hypothesis for preterm brain injury.

Higher brain dysfunction, such as language delay, is a major concern among preterm infants. Cerebral substrates of cognitive development in preterm infants remain elusive, partly because of limited methods. The present study focuses on hemodynamic response patterns for brain function by using near-infrared spectroscopy. Specifically, the study investigates gestational differences in the hemodynamic response pattern evoked in response to phonetic changes of speech and cerebral hemispheric specialization of the auditory area in preterm infants (n = 60) and term infants (n = 20). Eighty neonates born between 26 and 41 weeks of gestational age (GA) were tested from 33 to 41 weeks of postmenstrual age (PMA). We analyzed the hemodynamic response pattern to phonemic and prosodic contrasts for multiple channels on temporal regions and the laterality index of the auditory area. Preterm infants younger than 39 weeks of PMA showed significantly atypical hemodynamic patterns, with an inverted response shape. Partial correlation analysis of the typicality score of hemodynamic response revealed a significant positive correlation with PMA. The laterality index of preterm infants from 39 weeks of PMA demonstrated a tendency rightward dominance for prosodic changes similar to term infants. We provide new evidence that alterations in hemodynamic regulation and the functional system for phonemic and prosodic processing in preterm infants catch up by their projected due dates., Highlights • Hemodynamic responses to speech were examined in 80 preterm and term neonates. • fNIRS measured hemispheric specialization to phonemic and prosodic contrasts. • Some preterm infants showed atypical hemodynamics with an inverted response shape. • Postmenstrual age was related to hemodynamic patterns and functional lateralization. • Functional hemodynamic regulation of preterm infants caught up by the expected dates.

INTRODUCTION: The dynamic nature and complexity of the cellular events that take place during the last trimester of pregnancy make the developing cortex particularly vulnerable to perturbations. Abrupt interruption to normal gestation can lead to significant deviations to many of these processes, resulting in atypical trajectory of cortical maturation in preterm birth survivors. METHODS: We sought to first map typical cortical micro- and macrostructure development using invivo MRI in a large sample of healthy term-born infants scanned after birth (n = 259). Then we offer a comprehensive characterization of the cortical consequences of preterm birth in 76 preterm infants scanned at term-equivalent age (37-44 weeks postmenstrual age). We describe the group-average atypicality, the heterogeneity across individual preterm infants, and relate individual deviations from normative development to age at birth and neurodevelopment at 18 months. RESULTS: In the term-born neonatal brain, we observed heterogeneous and regionally specific associations between age at scan and measures of cortical morphology and microstructure, including rapid surface expansion, greater cortical thickness, lower cortical anisotropy and higher neurite orientation dispersion. By term-equivalent age, preterm infants had on average increased cortical tissue water content and reduced neurite density index in the posterior parts of the cortex, and greater cortical thickness anteriorly compared to term-born infants. While individual preterm infants were more likely to show extreme deviations (over 3.1 standard deviations) from normative cortical maturation compared to term-born infants, these extreme deviations were highly variable and showed very little spatial overlap between individuals. Measures of regional cortical development were associated with age at birth, but not with neurodevelopment at 18 months. CONCLUSION: We showed that preterm birth alters cortical micro- and macrostructural maturation near the time of full-term birth. Deviations from normative development were highly variable between individual preterm infants. ispartof: NEUROIMAGE vol:243 ispartof: location:United States status: published

Highlights • Surgical stress causes disruption of the gut barrier and microbiome. • In neonates intestinal dysbiosis increases risk for feeding intolerance, prolonged use of parenteral nutrition, and post-operative infection. • Probiotics prevent bacterial overgrowth, promote gut barrier function, and modulate the local immune response. • Monitoring dynamic changes in microbiome of post-surgical infants who received probiotics and placebo will provide with important information about gut colonization. • This study will assess the effect of probiotics on length of hospital stay, duration of parenteral nutrition, and feed tolerance in post-surgical infants., Any manipulation on open bowel causes interventional impact on gut microbiome, and surgical stress triggers bacterial translocation; thus, it will be fundamental to determine gut microbiome after surgery. Monitoring dynamic changes in microbiome of post-surgical infants who received probiotics and placebo could provide with important information about gut colonization and potential bacterial overgrowth. The purpose of this study is to assess the effect of probiotics supplementation on length of hospital stay, duration of parenteral nutrition, and feed tolerance in neonates after gastrointestinal surgery.

Preterm infants are at high risk of neurodevelopmental impairment, which may be due to altered development of brain connectivity. We aimed to (i) assess structural brain development from 25 to 45 weeks gestational age (GA) using graph theoretical approaches and (ii) test the hypothesis that preterm birth results in altered white matter network topology. Sixty-five infants underwent MRI between 25+3 and 45+6 weeks GA. Structural networks were constructed using constrained spherical deconvolution tractography and were weighted by measures of white matter microstructure (fractional anisotropy, neurite density and orientation dispersion index). We observed regional differences in brain maturation, with connections to and from deep grey matter showing most rapid developmental changes during this period. Intra-frontal, frontal to cingulate, frontal to caudate and inter-hemispheric connections matured more slowly. We demonstrated a core of key connections that was not affected by GA at birth. However, local connectivity involving thalamus, cerebellum, superior frontal lobe, cingulate gyrus and short range cortico-cortical connections was related to the degree of prematurity and contributed to altered global topology of the structural brain network. The relative preservation of core connections at the expense of local connections may support more effective use of impaired white matter reserve following preterm birth., Graphical abstract fx1, Highlights • First characterisation of preterm brain networks weighted by microstructural features. • Preterm brain is resistant to disruptions in development of core connections. • Peripheral connections associated with cognition and behaviour are more vulnerable.

Highlights • Maturation of specific WM tracts in preterm individuals differs from those of term controls. • The elastic net logistic regression model was used to identify altered white matter tracts in the preterm brain. • The alteration of the cingulum in the preterm at near-term correlate with neurodevelopmental scores at 18–22 months of age., Background Relative to full-term infants, very preterm infants exhibit disrupted white matter (WM) maturation and problems related to development, including motor, cognitive, social-emotional, and receptive and expressive language processing. Objective The present study aimed to determine whether regional abnormalities in the WM microstructure of very preterm infants, as defined relative to those of full-term infants at a near-term age, are associated with neurodevelopmental outcomes at the age of 18–22 months. Methods We prospectively enrolled 89 very preterm infants (birth weight

Children born very preterm (VPT, Highlights • Very preterm children have widespread decreased MTR in white matter. • T1-w/T2-w ratio measures showed consistent white matter alterations. • T1-w/T2-w ratio was also reduced in subcortical, occipital and temporal regions. • MTR and T1-w/T2-w were correlated throughout the brain. • MTR and T1-w/T2-w correlated with developmental assessments.

Introduction: Preterm infants are at increased risk of osteopenia of prematurity due to insufficient bone mineral accretion. Data on long term effects of prematurity on bone health are conflicting. This study aimed to compare bone mineral density (BMD) in young adults born very preterm and full-term controls and to examine factors associated with long-term bone health. Methods: This observational cross-sectional study enrolled 101 young adults (18–29 years) born

Objective We combined diffusion MRI (dMRI) with quantitative T1 (qT1) relaxometry in a sample of school-aged children born preterm and full term to determine whether reduced fractional anisotropy (FA) within the corpus callosum of the preterm group could be explained by a reduction in myelin content, as indexed by R1 (1/T1) from qT1 scans. Methods 8-year-old children born preterm (n = 29; GA 22–32 weeks) and full term (n = 24) underwent dMRI and qT1 scans. Four subdivisions of the corpus callosum were segmented in individual native space according to cortical projection zones (occipital, temporal, motor and anterior-frontal). Fractional anisotropy (FA) and R1 were quantified along the tract trajectory of each subdivision and compared across two birth groups. Results Compared to controls, preterm children demonstrated significantly decreased FA in 3 of 4 analyzed corpus callosum subdivisions (temporal, motor, and anterior frontal segments) and decreased R1 in only 2 of 4 corpus callosum subdivisions (temporal and motor segments). FA and RD were significantly associated with R1 within temporal but not anterior frontal subdivisions of the corpus callosum in the term group; RD correlated with R1 in the anterior subdivision in the preterm group only. Conclusions Myelin content, as indexed by R1, drives some but not all of the differences in white matter between preterm and term born children. Other factors, such as axonal diameter and directional coherence, likely contributed to FA differences in the anterior frontal segment of the corpus callosum that were not well explained by R1., Highlights • Reduced FA in 3 corpus callosum segments may relate to myelin or axonal factors. • Reduced R1 in PT children in 2 corpus callosum segments suggests reduced myelin. • Reduced R1 explains reduced FA in the posterior but not anterior corpus callosum. • Changes in myelin content explain some but not all white matter differences in PT.

Background Risk of morbidity differs between very preterm (VP, Highlights • The very, moderate, and late preterm brain differed from full-term at term. • Differences were seen for CSF, temporal grey and white, and corpus callosum volumes. • Differences were also found in the microstructure of many major white matter tracts. • Differences were most pronounced for very and least for late preterm infants.

Introduction Induced birth of fetuses with gastroschisis from 34 weeks gestational age (GA) has been proposed to reduce bowel damage. We aimed to determine the effect of birth timing on time to full enteral feeds (ENT), length of hospital stay (LOS), and sepsis. Methods A retrospective analysis (2000–2014) of gastroschisis born at ≥ 34 weeks GA was performed. Associations between birth timing and outcomes were analyzed by Mann–Whitney test, Cox regression, and Fisher's exact test. Results 217 patients were analyzed. Although there was no difference in ENT between those born at 34–36 + 6 weeks GA (median 28 range [6–639] days) compared with ≥ 37 weeks GA (27 [8–349] days) when analyzed by Mann–Whitney test (p = 0.5), Cox regression analysis revealed that lower birth GA significantly prolonged ENT (p = 0.001). LOS was significantly longer in those born at 34–36 + 6 weeks GA (42 [8–346] days) compared with ≥ 37 weeks GA 34 [11–349] days by both Mann–Whitney (p = 0.02) and Cox regression analysis (p

Very preterm birth is associated with altered white matter microstructure and language difficulties, which may compromise communication, social function and academic achievement, but the relationship between these two factors is unclear. The aim of this study was to explore associations between white matter microstructure and language domains of semantics, grammar and phonological awareness at 7-years of age on a whole-brain level and within the arcuate fasciculus, an important language pathway, in very preterm and term-born children. Language was assessed in 145 very preterm-born (, Highlights • White matter microstructure related to language in very preterm children and controls. • Widespread white matter tracts, including the arcuate fasciculus were involved. • Higher fractional anisotropy and axon density correlated with better language performance. • Lower axial, radial and mean diffusivity related to better semantics, grammar and phonological awareness.

Highlights • Laser therapy for fetal reduction could be associate with Aplasia Cutis Congenita. • Despite of size of lesion conservative treatment could be an effective option. • Extreme prematurity did not affected degree of spontaneous epithelization. • Patient was followed up to 5 years and no complications were detected., Monochorionic (MC) twin pregnancies are known to carry a high risk of twin-to-twin transfusion syndrome (TTTS) that could lead to miscarriage and perinatal death. Demise of one fetus is frequently associated with co-fetal death. Fetal reduction by interstitial laser therapy is an effective procedure to prevent this outcome, but it may be associated with significant risks for both mother and fetus. Aplasia Cutis Congenita (ACC) may occur in up to 8% cases of fetal reduction by laser therapy. We report ACC in a preterm infant, a survivor of interstitial laser therapy for fetal reduction in MC pregnancy. Despite of massive skin lesions we were able to manage this case conservatively. Follow-up at 5 years of age revealed minimal scarring and no motor function limitations.

Highlights • Longitudinal DTI data were collected in very preterm (VPT) and full-term children. • We found disruptions in the posterior visual system of the VPT children. • Early life maturational deficits were found in an anophthalmic VPT child. • Preterm birth and monocular vision jointly impact neuroanatomical development. • Between birth and 8yrs of age, considerable compensatory mechanisms are evident., Anophthalmia, characterized by the absence of an eye(s), is a rare major birth defect with a relatively unexplored neuroanatomy. Longitudinal comparison of white matter development in an anophthalmic (AC) very preterm (VPT) child with both binocular VPT and full-term (FT) children provides unique insights into early neurodevelopment of the visual system. VPT-born neonates (

Structural brain abnormalities identified at near-term age have been recognized as potential predictors of neurodevelopment in children born preterm. The aim of this study was to examine the relationship between neonatal physiological risk factors and early brain structure in very-low-birth-weight (VLBW) preterm infants using structural MRI and diffusion tensor imaging (DTI) at near-term age. Structural brain MRI, diffusion-weighted scans, and neonatal physiological risk factors were analyzed in a cross-sectional sample of 102 VLBW preterm infants (BW ≤ 1500 g, gestational age (GA) ≤ 32 weeks), who were admitted to the Lucile Packard Children's Hospital, Stanford NICU and recruited to participate prior to routine near-term brain MRI conducted at 36.6 ± 1.8 weeks postmenstrual age (PMA) from 2010 to 2011; 66/102 also underwent a diffusion-weighted scan. Brain abnormalities were assessed qualitatively on structural MRI, and white matter (WM) microstructure was analyzed quantitatively on DTI in six subcortical regions defined by DiffeoMap neonatal brain atlas. Specific regions of interest included the genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, the thalamus, and the globus pallidus. Regional fractional anisotropy (FA) and mean diffusivity (MD) were calculated using DTI data and examined in relation to neonatal physiological risk factors including gestational age (GA), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and sepsis, as well as serum levels of C-reactive protein (CRP), glucose, albumin, and total bilirubin. Brain abnormalities were observed on structural MRI in 38/102 infants including 35% of females and 40% of males. Infants with brain abnormalities observed on MRI had higher incidence of BPD (42% vs. 25%) and sepsis (21% vs. 6%) and higher mean and peak serum CRP levels, respectively, (0.64 vs. 0.34 mg/dL, p = .008; 1.57 vs. 0.67 mg/dL, p= .006) compared to those without. The number of signal abnormalities observed on structural MRI correlated to mean and peak CRP (rho = .316, p = .002; rho = .318, p= .002). The number of signal abnormalities observed on MRI correlated with thalamus MD (left: r= .382, p= .002; right: r= .400, p= .001), controlling for PMA-at-scan. Thalamus WM microstructure demonstrated the strongest associations with neonatal risk factors. Higher thalamus MD on the left and right, respectively, was associated with lower GA (r = −.322, p = .009; r= −.381, p= .002), lower mean albumin (r = −.276, p= .029; r= −.385, p= .002), and lower mean bilirubin (r = −.293, p= .020; r= −.337 p= .007). Results suggest that at near-term age, thalamus WM microstructure may be particularly vulnerable to certain neonatal risk factors. Interactions between albumin, bilirubin, phototherapy, and brain development warrant further investigation. Identification of physiological risk factors associated with selective vulnerability of certain brain regions at near-term age may clarify the etiology of neurodevelopmental impairment and inform neuroprotective treatment for VLBW preterm infants., Highlights • Biomarkers of inflammation in preterm infants correlated with brain abnormalities detected on near-term structural MRI. • Biomarkers of inflammation in preterm infants correlated with near-term WM microstructure assessed on DTI. • Signal abnormalities observed on near-term structural MRI correlated with increased thalamus MD.

Objective Minimally invasive autopsy using post-mortem magnetic resonance imaging (MRI) is a valid alternative to conventional autopsy in fetuses and infants. Estimation of brain weight is an integral part of autopsy, but manual segmentation of organ volumes on MRI is labor intensive and prone to errors, therefore unsuitable for routine clinical practice. In this paper we aim to show that volumetric measurements of the post-mortem fetal and neonatal brain can be accurately estimated using semi-automatic techniques and a high correlation can be found with the weights measured from conventional autopsy results. Methods The brains of 17 newborn subjects, part of Magnetic Resonance Imaging Autopsy Study (MaRIAS), were segmented from post-mortem MR images into cerebrum, cerebellum and brainstem using a publicly available neonate brain atlas and semi-automatic segmentation algorithm. The results of the segmentation were averaged to create a new atlas, which was then used for the automated atlas-based segmentation of 17 MaRIAS fetus subjects. As validation, we manually segmented the MR images from 8 subjects of each cohort and compared them with the automatic ones. The semi-automatic estimation of cerebrum weight was compared with the results of the conventional autopsy. Results The Dice overlaps between the manual and automatic segmentations are 0.991 and 0.992 for cerebrum, 0.873 and 0.888 for cerebellum and 0.819 and 0.815 for brainstem, for newborns and fetuses, respectively. Excellent agreement was obtained between the estimated MR weights and autopsy gold standard ones: mean absolute difference of 5 g and 2% maximum error for the fetus cohort and mean absolute difference of 20 g and 11% maximum error for the newborn one. Conclusions The high correlation between the obtained segmentation and autopsy weights strengthens the idea of using post-mortem MRI as an alternative for conventional autopsy of the brain., Highlights • We segment the cerebrum of 17 newborns and 17 fetuses from postmortem MR. • There is high correlation between the autopsy and MR segmentation brain volumes. • Postmortem MR can be a non-invasive alternative to conventional autopsy of infants.

Children born very preterm (VPT) are at risk for visual impairments, the main risk factors being retinopathy of prematurity and cerebral white matter injury, however these only partially account for visual impairments in VPT children. This study aimed to compare optic radiation microstructure and volume between VPT and term-born children, and to investigate associations between 1) perinatal variables and optic radiations; 2) optic radiations and visual function in VPT children. We hypothesized that optic radiation microstructure would be altered in VPT children, predicted by neonatal cerebral white matter abnormality and retinopathy of prematurity, and associated with visual impairments. 142 VPT children and 32 controls underwent diffusion-weighted magnetic resonance imaging at 7 years of age. Optic radiations were delineated using constrained spherical deconvolution tractography. Tract volume and average diffusion tensor values for the whole optic radiations and three sub-regions were compared between the VPT and control groups, and correlated with perinatal variables and 7-year visual outcome data. Total tract volumes and average diffusion values were similar between VPT and control groups. On regional analysis of the optic radiation, mean and radial diffusivity were higher within the middle sub-regions in VPT compared with control children. Neonatal white matter abnormalities and retinopathy of prematurity were associated with optic radiation diffusion values. Lower fractional anisotropy in the anterior sub-regions was associated with poor visual acuity and increased likelihood of other visual defects. This study presents evidence for microstructural alterations in the optic radiations of VPT children, which are largely predicted by white matter abnormality or severe retinopathy of prematurity, and may partially explain the higher rate of visual impairments in VPT children., Highlights • This study compares optic radiations between very preterm and control 7-year-olds. • There are microstructural alterations in the optic radiations of VPT children. • The main risk factors are retinopathy of prematurity and white matter injury. • Microstructural alterations associate with poor visual acuity and visual defects. • This study elucidates neuroanatomical correlates of visual impairment in prematurity.

The brainstem, critical for motor function, autonomic regulation, and many neurocognitive functions, undergoes rapid development from the third trimester. Accordingly, we hypothesized it would be vulnerable to insult during this period, and that a difficult clinical course in the neonatal intensive care unit (NICU) would affect development, and be reflected through atypical shape. Our study population consisted of 66 neonates – all inpatients from the NICU at Victoria Hospital, London Health Sciences Centre, ON, Canada, of which 45 entered the final analysis. The cohort varied in gestational age (GA) and ranged from neurologically healthy to severely brain-injured. Structural MRI was used to quantify brainstem shape at term-equivalent age. From these images, brainstems were semi-automatically segmented and co-registered across subjects. The anterior-posterior dimensions on a sagittal maximum intensity projection were used as the basis for shape comparison. Factor analysis was used to summarize variation in shape and in clinical course to determine three shape factors and three clinical factors, and their relationship assessed using correlation. A factor driven by low GA and associated complications correlated with alterations in the posterior medulla, while a factor driven by complications independent of GA correlated with alterations in the midbrain. Additionally, single clinical measures most representative of their respective clinical factor (days in NICU; days on ventilation) predicted the changes. Thus, different clinical courses in the NICU may have different effects on the shape of the brainstem, and may mediate some of the distinct neurodevelopmental profiles observed in premature and brain-injured neonates., Highlights • Gestational age & complications correlated with posterior medulla alterations • Complications independent of gestational age correlated with midbrain alterations • Single clinical measures representative of their clinical factor predicted changes • Different NICU clinical courses found to have distinct effects on brainstem shape

Objective To determine whether the spatial extent and location of early-identified punctate white matter injury (WMI) is associated with regionally-specific disruptions in thalamocortical-connectivity in very-preterm born neonates. Methods 37 very-preterm born neonates (median gestational age: 28.1 weeks; interquartile range [IQR]: 27–30) underwent early MRI (median age 32.9 weeks; IQR: 32–35), and WMI was identified in 13 (35%) neonates. Structural T1-weighted, resting-state functional Magnetic Resonance Imaging (rs-fMRI, n = 34) and Diffusion Tensor Imaging (DTI, n = 31) sequences were acquired using 3 T-MRI. A probabilistic map of WMI was developed for the 13 neonates demonstrating brain injury. A neonatal atlas was applied to the WMI maps, rs-fMRI and DTI analyses to extract volumetric, functional and microstructural data from regionally-specific brain areas. Associations of thalamocortical-network strength and alterations in fractional anisotropy (FA, a measure of white-matter microstructure) with WMI volume were assessed in general linear models, adjusting for age at scan and cerebral volumes. Results WMI volume in the superior (β = −0.007; p = .02) and posterior corona radiata (β = −0.01; p = .01), posterior thalamic radiations (β = −0.01; p = .005) and superior longitudinal fasciculus (β = −0.02; p = .001) was associated with reduced connectivity strength between thalamus and parietal resting-state networks. WMI volume in the left (β = −0.02; p = .02) and right superior corona radiata (β = −0.03; p = .008), left posterior corona radiata (β = −0.03; p = .01), corpus callosum (β = −0.11; p, Highlights • Lesions in white matter pathways predicted altered functional connectivity. • White matter lesions predicted alterations in white matter microstructure. • Findings of lesion location and size were regionally-specific. • White matter lesion size and location may underlie later delays in development.

Objective To investigate the association between sustained maternal depression at 12, 24, and 48 months post-partum and child anthropometry at age of 4 years. Study design A total of 99.2% of the 4287 children born in 2004 in Pelotas, Brazil, were enrolled in a cohort study. At 3, 12, 24, and 48 months, mothers were interviewed and provided information on several characteristics. Maternal depression was investigated through the Edinburgh Postnatal Depression Scale (EPDS). Weight-for-age, height-for-age, and weight-for-height z-scores at 48 months, according to World Health Organization growth curves, were the outcomes. Multivariate analyses were conducted through logistic regression. Results At the 48-month follow-up, of the 3792 children, prevalence of underweight was 1.7%; stunting, 3.6%; wasting, 0.6%; and overweight, 12.2%. Depression (EPDS ≥13) was observed in 17.9% of the 3748 mothers. Of the mothers, 4.7% were persistently depressed at the 12-, 24-, and 48-month visits. In crude analyses, maternal depression was positively associated with underweight and stunting. After adjustment, maternal depression was not associated with any of the anthropometric indices. Conclusion Long-lasting maternal depression at 12, 24, and 48 months post-partum is not a risk factor for impaired child growth or overweight at age of 4 years.

Very preterm birth is associated with an increased prevalence of attention problems and may especially impair executive attention, i.e., top-down control of attentional selection in situations where distracting information interferes with the processing of task-relevant stimuli. While there are initial findings linking structural brain alterations in preterm-born individuals with attention problems, the functional basis of these problems are not well understood. The present study used an fMRI adaptation of the Attentional Network Test to examine the neural correlates of executive attention in a large sample of N = 86 adults born very preterm and/or with very low birth weight (VP/VLBW), and N = 100 term-born controls. Executive attention was measured by comparing task behavior and brain activations associated with the processing of incongruent vs. congruent arrow flanker stimuli. Consistent with subtle impairments of executive attention, the VP/VLBW group showed lower accuracy and a tendency for increased response times during the processing of incongruent stimuli. Both groups showed similar activation patters, especially within expected fronto-cingulo-parietal areas, but no significant between-group differences. Our results argue for a maintained attention-relevant network organization in high-functioning preterm born adults in spite of subtle deficits in executive attention. Gestational age and neonatal treatment variables showed associations with task behavior, and brain activation in the dorsal ACC and lateral occipital areas, suggesting that the degree of prematurity (and related neonatal complications) has subtle modulatory influences on executive attention processing., Highlights • fMRI study examines neural correlates of executive attention in preterm-born adults. • Preterm-born adults show subtle behavioral deficits. • Preterm-born adults show maintained organization of attention-related networks. • Modulatory effects of gestational age and neonatal treatment variables are observed.

Objectives To measure both fractional anisotropy (FA) values in the corticospinal tracts (CSTs) and volume of the thalami in preterm infants with cystic periventricular leukomalacia (c-PVL) and to compare these measurements with control infants. Study design Preterm infants with c-PVL and controls with magnetic resonance imaging data acquired between birth and term equivalent age (TEA) were retrospectively identified in 2 centers. Tractography of the CST and segmentation of the thalamus were performed, and values from infants with c-PVL and controls were compared. Results Thirty-three subjects with c-PVL and 31 preterm controls were identified. All had at least 1 scan up to TEA, and multiple scans were performed in 31 infants. A significant difference in FA values of the CST was found between cases and controls on the scans both before and at TEA. Absolute thalamic volumes were significantly reduced at TEA but not on the earlier scans. Data acquired in infancy showed lower FA values in infants with c-PVL. Conclusions Damage to the CST can be identified on the early scan and persists, whereas the changes in thalamic volume develop in the weeks between the early and term equivalent magnetic resonance imaging. This may reflect the difference between acute and remote effects of the extensive injury to the white matter caused by c-PVL.

Background: It is well documented that overt hypothyroidism is associated with adverse pregnancy outcomes, but studies of subclinical hypothyroidism have demonstrated conflicting results. Objective: Thyroid hormones are known to regulate mitochondrial function, and the aim of this study was to examine the possible relationship of subclinical hypothyroidism and mitochondrial dysfunction to adverse pregnancy outcomes in pregnant women. Methods: Women in their third trimester of pregnancy (n = 113) who did not receive thyroid medication were included in this cross-sectional study. All participants were interviewed, and their thyroid status was determined. All participants had concentrations of thyroid hormones (fT 4 and tT 3) within the reference range. In addition to thyroid status, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were measured by flow cytometry. To establish a reference range of MMP and ROS, a group of euthyroid, nonpregnant women were used as euthyroid controls. Adverse pregnancy outcome was defined as preterm delivery, preeclampsia, placental abruption, Apgar score

Objective To assess the impact of being born preterm or small for gestational age (SGA) on several adult outcomes. Study design We analyzed data for 4518 adult participants in 5 birth cohorts from Brazil, Guatemala, India, the Philippines, and South Africa. Results In the study population, 12.8% of males and 11.9% of females were born preterm, and 26.8% of males and 22.4% of females were born term but SGA. Adults born preterm were 1.11 cm shorter (95% CI, 0.57-1.65 cm), and those born term but SGA were 2.35 cm shorter (95% CI, 1.93-2.77 cm) compared with those born at term and appropriate size for gestational age. Blood pressure and blood glucose level did not differ by birth category. Compared with those born term and at appropriate size for gestational age, schooling attainment was 0.44 years lower (95% CI, 0.17-0.71 years) in those born preterm and 0.41 years lower (95% CI, 0.20-0.62 years) in those born term but SGA. Conclusion Being born preterm or term but SGA is associated with persistent deficits in adult height and schooling, but is not related to blood pressure or blood glucose level in low- and middle-income settings. Increased postnatal growth is associated with gains in height and schooling regardless of birth status, but not with increases in blood pressure or blood glucose level.

Objective:\ud To determine whether general cognitive ability, basic mathematic processing, and mathematic attainment are universally affected by gestation at birth, as well as whether mathematic attainment is more strongly associated with cohort-specific factors such as schooling than basic cognitive and mathematical abilities.\ud \ud Study design:\ud The Bavarian Longitudinal Study (BLS, 1289 children, 27-41 weeks gestational age [GA]) was used to estimate effects of GA on IQ, basic mathematic processing, and mathematic attainment. These estimations were used to predict IQ, mathematic processing, and mathematic attainment in the EPICure Study (171 children