ABCnet: Adversarial bias correction network for infant brain MR images.

Automatic correction of intensity nonuniformity (also termed as the bias correction) is an essential step in brain MR image analysis. Existing methods are typically developed for adult brain MR images based on the assumption that the image intensities within the same brain tissue are relatively uniform. However, this assumption is not valid in infant brain MR images, due to the dynamic and regionally-heterogeneous image contrast and appearance changes, which are caused by the underlying spatiotemporally-nonuniform myelination process. Therefore, it is not appropriate to directly use existing methods to correct the infant brain MR images. In this paper, we propose an end-to-end 3D adversarial bias correction network (ABCnet), tailored for direct prediction of bias fields from the input infant brain MR images for bias correction. The "ground-truth" bias fields for training our network are carefully defined by an improved N4 method, which integrates manually-corrected tissue segmentation maps as anatomical prior knowledge. The whole network is trained alternatively by minimizing generative and adversarial losses. To handle the heterogeneous intensity changes, our generative loss includes a tissue-aware local intensity uniformity term to reduce the local intensity variation in the corrected image. Besides, it also integrates two additional terms to enhance the smoothness of the estimated bias field and to improve the robustness of the proposed method, respectively. Comprehensive experiments with different sizes of training datasets have been carried out on a total of 1492 T1w and T2w MR images from neonates, infants, and adults, respectively. Both qualitative and quantitative evaluations on simulated and real datasets consistently demonstrate the superior performance of our ABCnet in both accuracy and efficiency, compared with popularly available methods.

Radiation safety education and diagnostic imaging in pediatric patients with surgically treated hydrocephalus: the patient and family perspective.

PURPOSE: Surgically treated hydrocephalus patients are frequently imaged with head computed tomography (CT), and risk/benefit communication with families is inconsistent and unknown. We aimed to educate patients and caregivers about radiation safety in CT and explore their communication preferences. METHODS: We conducted a pediatric CT radiation safety and diagnostic imaging educational workshop for patients and caregivers at a national conference on hydrocephalus to characterize current practice and desired communication about CT imaging. Our workshop consisted of an interactive educational intervention with pre-/post-session surveys followed by feedback from participants. RESULTS: Our session included 34 participants (100% response rate for surveys) with 28 being parents of individuals with hydrocephalus. A total of 76% (n = 26) participants showed an increase in knowledge after the session (p < 0.01). All participants (N = 34) uniformly desired risk/benefit discussions before CT scans. However, 71% stated that they were not informed of risks/benefits of CT scans by a medical professional. Following the session, the number of participants indicating that informed consent should be obtained before CT scans increased from 30 to 33. Respondents also revealed that 14% of children and young adults had received > 100 CT scans for shunt evaluation with the median being 25 scans (IQR 20). CONCLUSIONS: Caregivers desire and deserve to be empowered through education and social support, and continuously engaged through sharing decisions and co-designing care plans. The neurosurgical community is in an ideal position to collaborate with radiologists, primary care providers, and parents in the development and testing of credible, high-quality online and social media resources.

Subdural Hemorrhage in Asymptomatic Neonates: Neurodevelopmental Outcomes and MRI Findings at 2 Years.

Background Subdural hemorrhage (SDH) is thought to have a benign course in asymptomatic neonates. However, effects on neurodevelopmental outcomes have not been established. Purpose To evaluate neurodevelopmental outcomes, gray matter volumes, and MRI findings in asymptomatic neonates with SDH compared with control neonates. Materials and Methods This retrospective analysis was conducted between 2003 and 2016 and was based on data from the University of North Carolina Early Brain Development Study. Neurodevelopmental outcomes were evaluated at 2 years of age by using the Mullen Scales of Early Learning (MSEL). All infants were imaged with 3.0-T MRI machines and were evaluated for SDH at baseline (neonates) and at ages 1 and 2 years. Volumetric MRI for brain segmentation was performed at ages 1 and 2 years. A secondary analysis was performed in neonates matched 1:1 with control neonates. Differences in categorical variables were measured by using the Fisher exact test, and the t test was used for continuous variables. Results A total of 311 neonates (mean gestational age ± standard deviation, 39.3 weeks ± 1.5), including 57 with SDH (mean gestational age, 39.5 weeks ± 1.2), were evaluated. The subgroup included 55 neonates with SDH (mean gestational age, 39.6 weeks ± 1.2) and 55 matched control neonates (mean gestational age, 39.7 weeks ± 1.2). Fifty-five of 57 neonates with SDH (97%; 95% CI: 92, 100) were delivered vaginally compared with 157 of 254 control neonates (62%, 95% CI: 56, 68; P < .001). Otherwise, there were no differences in perinatal, maternal, or obstetric parameters. There were no differences in composite MSEL scores (115 ± 15 and 109 ± 16 at 2 years, respectively; P = .05) or gray matter volumes between the neonatal SDH group and control neonates (730 cm3 ± 85 and 742 cm3 ± 76 at 2 years, respectively; P = .70). There was no evidence of rebleeding at follow-up MRI. Conclusion Neurodevelopmental scores and gray matter volumes at age 2 years did not differ between asymptomatic neonates with subdural hemorrhage and control neonates. © RSNA, 2020 Online supplemental material is available for this article.

Disentangled-Multimodal Adversarial Autoencoder: Application to Infant Age Prediction With Incomplete Multimodal Neuroimages.

Effective fusion of structural magnetic resonance imaging (sMRI) and functional magnetic resonance imaging (fMRI) data has the potential to boost the accuracy of infant age prediction thanks to the complementary information provided by different imaging modalities. However, functional connectivity measured by fMRI during infancy is largely immature and noisy compared to the morphological features from sMRI, thus making the sMRI and fMRI fusion for infant brain analysis extremely challenging. With the conventional multimodal fusion strategies, adding fMRI data for age prediction has a high risk of introducing more noises than useful features, which would lead to reduced accuracy than that merely using sMRI data. To address this issue, we develop a novel model termed as disentangled-multimodal adversarial autoencoder (DMM-AAE) for infant age prediction based on multimodal brain MRI. Specifically, we disentangle the latent variables of autoencoder into common and specific codes to represent the shared and complementary information among modalities, respectively. Then, cross-reconstruction requirement and common-specific distance ratio loss are designed as regularizations to ensure the effectiveness and thoroughness of the disentanglement. By arranging relatively independent autoencoders to separate the modalities and employing disentanglement under cross-reconstruction requirement to integrate them, our DMM-AAE method effectively restrains the possible interference cross modalities, while realizing effective information fusion. Taking advantage of the latent variable disentanglement, a new strategy is further proposed and embedded into DMM-AAE to address the issue of incompleteness of the multimodal neuroimages, which can also be used as an independent algorithm for missing modality imputation. By taking six types of cortical morphometric features from sMRI and brain functional connectivity from fMRI as predictors, the superiority of the proposed DMM-AAE is validated on infant age (35 to 848 days after birth) prediction using incomplete multimodal neuroimages. The mean absolute error of the prediction based on DMM-AAE reaches 37.6 days, outperforming state-of-the-art methods. Generally, our proposed DMM-AAE can serve as a promising model for prediction with multimodal data.

Radiology Resident Journal Club: Enhancements Add Educational Value.

RATIONALE AND OBJECTIVES: Resident journal clubs are essential to develop skills to critically appraise existing literature. However, most reports of journal clubs focus on logistics of the activity and less on established roles of those involved. Our objective is to report on an innovative journal club from the perspective of key participants. MATERIALS AND METHODS: Journal club schedule, assignments, evaluations, and analysis are proffered from our institution. The journal club goals were formulated as: (1) improving resident understanding of research (biostatistical and epidemiologic) methods and statistical concepts, (2) teaching critical appraisal skills, and (3) promoting the use of evidence-based medicine. Each session's format is interactive, consisting of a 10 minute lecture with radiology examples of a research or statistical concept, followed by a journal club style discussion. Crucial to the success of this curriculum has been input and engagement of multiple parties: radiology residents, epidemiologist directors, and subspecialist clinician educator faculty members. CONCLUSION: A well-thought out and well-run resident journal club offers numerous solutions to radiology residencies. To residency program leadership and to each individual resident annually, resident journal club offers cutting edge medical knowledge, interactive conferences in the formal didactic curriculum, resident training in critical thinking skills and research design, resident training in interpersonal and communication skills, opportunity for residents to be teachers, and expanded resident interprofessional education. It meets Accreditation Council for Graduate Medical Education common program, Residency Review Committee diagnostic radiology program, and American Board of Radiology Milestones requirements.

The UNC/UMN Baby Connectome Project (BCP): An overview of the study design and protocol development.

The human brain undergoes extensive and dynamic growth during the first years of life. The UNC/UMN Baby Connectome Project (BCP), one of the Lifespan Connectome Projects funded by NIH, is an ongoing study jointly conducted by investigators at the University of North Carolina at Chapel Hill and the University of Minnesota. The primary objective of the BCP is to characterize brain and behavioral development in typically developing infants across the first 5 years of life. The ultimate goals are to chart emerging patterns of structural and functional connectivity during this period, map brain-behavior associations, and establish a foundation from which to further explore trajectories of health and disease. To accomplish these goals, we are combining state of the art MRI acquisition and analysis techniques, including high-resolution structural MRI (T1-and T2-weighted images), diffusion imaging (dMRI), and resting state functional connectivity MRI (rfMRI). While the overall design of the BCP largely is built on the protocol developed by the Lifespan Human Connectome Project (HCP), given the unique age range of the BCP cohort, additional optimization of imaging parameters and consideration of an age appropriate battery of behavioral assessments were needed. Here we provide the overall study protocol, including approaches for subject recruitment, strategies for imaging typically developing children 0-5 years of age without sedation, imaging protocol and optimization, a description of the battery of behavioral assessments, and QA/QC procedures. Combining HCP inspired neuroimaging data with well-established behavioral assessments during this time period will yield an invaluable resource for the scientific community.

Maximizing Benefit and Minimizing Risk in Medical Imaging Use: An Educational Primer for Health Care Professions Students.

"I am not young enough to know everything."Oscar Wilde. BACKGROUND: There is insufficient knowledge among providers and patients/caregivers of ionizing radiation exposure from medical imaging examinations. This study used a brief, interactive educational intervention targeting the topics of best imaging practices and radiation safety early in health professions students' training. The authors hypothesized that public health, medical, and physician assistant students who receive early education for imaging appropriateness and radiation safety will undergo a change in attitude and have increased awareness and knowledge of these topics. MATERIALS AND METHODS: The authors conducted a 1.5-hour interactive educational intervention focusing on medical imaging utilization and radiation safety. Students were presented with a pre/postquestionnaire and data were analyzed using t tests and multivariate analysis of variance. RESULTS: A total of 301 students were enrolled in the study. There was 58% (P < .01) and 85% (P < .01) improvement in attitude and knowledge regarding appropriateness of imaging, respectively. The authors also found an 8% increase (P < .01) in students who thought informed consent should be obtained prior to pediatric computed tomographic imaging. Physical assistant students were more likely than medical students to prefer obtaining informed consent at baseline (P = .03). CONCLUSIONS: A brief educational session provided to health professions students early in their education showed an increased awareness and knowledge of the utility, limitations, and risks associated with medical imaging. Incorporation of a best imagining practice educational session early during medical education may promote more thoughtful imaging decisions for future medical providers.

LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases.

PURPOSE: HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM. PATIENTS AND METHODS: Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%. RESULTS: 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2-5). OS was 12.2 mos (95% CI 0.6-20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS. CONCLUSION: While intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. CLINICAL TRIAL: (NCT01305941).

Effects of Career Duration, Concussion History, and Playing Position on White Matter Microstructure and Functional Neural Recruitment in Former College and Professional Football Athletes.

Purpose To better understand the relationship between exposure to concussive and subconcussive head impacts, white matter integrity, and functional task-related neural activity in former U.S. football athletes. Materials and Methods Between 2011 and 2013, 61 cognitively unimpaired former collegiate and professional football players (age range, 52-65 years) provided informed consent to participate in this cross-sectional study. Participants were stratified across three crossed factors: career duration, concussion history, and primary playing position. Fractional anisotropy (FA) and blood oxygen level-dependent (BOLD) percent signal change (PSC) were measured with diffusion-weighted and task-related functional magnetic resonance imaging, respectively. Analyses of variance of FA and BOLD PSC were used to determine main or interaction effects of the three factors. Results A significant interaction between career duration and concussion history was observed; former college players with more than three concussions had lower FA in a broadly distributed area of white matter compared with those with zero to one concussion (t29 = 2.774; adjusted P = .037), and the opposite was observed for former professional players (t29 = 3.883; adjusted P = .001). A separate interaction between concussion history and position was observed: Nonspeed players with more than three concussions had lower FA in frontal white matter compared with those with zero to one concussion (t25 = 3.861; adjusted P = .002). Analysis of working memory-task BOLD PSC revealed a similar interaction between concussion history and position (all adjusted P < .004). Overall, former players with lower FA tended to have lower BOLD PSC across three levels of a working memory task. Conclusion Career duration and primary playing position seem to modify the effects of concussion history on white matter structure and neural recruitment. The differences in brain structure and function were observed in the absence of clinical impairment, which suggested that multimodal imaging may provide early markers of onset of traumatic neurodegenerative disease. © RSNA, 2017 Online supplemental material is available for this article.

Working Face-to-Face for Pediatric CT Dose Reduction: A Community Toolkit.

Although children are especially vulnerable to the health risks of ionizing radiation, approximately 8 million CTs are performed on children in the USA. Widespread dose variation is common, particularly in non-pediatric focused facilities. In this article we present our rationale and hands-on approach in developing and refining a toolkit aimed at helping a community hospital with pediatric CT dose reduction.

A Toolkit for Pediatric CT Dose Reduction in Community Hospitals.

Pediatric CT radiation dose optimization is a challenging process for pediatric-focused facilities and community hospitals alike. Ongoing experience and trial-and-error approaches to dose reduction in the large academic hospital setting may position these centers to help community hospitals that strive for CT quality improvement. We describe our hands-on approach in a pilot project to create a partnership between an academic medical center and a community hospital to develop a toolkit for implementing CT dose reduction. Our aims were to (1) assess the acceptability of an interactive educational program and electronic toolkit booklet, (2) conduct a limited test of the efficacy of the toolkit in promoting knowledge and readiness to change, and (3) assess the acceptability and practicality of a collaborative approach to implementing dose reduction protocols in community hospitals. In partnering with the community hospital, we found that they had size-specific radiation doses two to three times higher than those at our center. Survey results after a site visit with interactive educational presentations revealed an increase in knowledge, stronger opinions about the health risks of radiation from CT scans, and willingness and perceived ability to reduce pediatric CT doses.

Frequency of spontaneous BOLD signal shifts during infancy and correlates with cognitive performance.

Numerous studies have been conducted to delineate the early development of different functional networks, based on measuring the temporal synchronization of spontaneous blood oxygenation level-dependent (BOLD) signals acquired using resting state functional MRI (rsfMRI). However, little attention has been paid to the change of the frequency properties of these signals during early brain development. Such frequency properties may reflect important physiological changes and potentially have significant cognitive consequences. In this study, leveraging a large (N=86 subjects), longitudinal sample of human infants scanned during the first two years of life, we aimed to specifically delineate the developmental changes of the frequency characteristics of spontaneous BOLD signals. Both whole-brain and network-level examinations were carried out and the frequency-behavior relationship was explored. Our results revealed a clear right-ward shift of BOLD signal frequency during the first year of life. Moreover, the power at the peak-frequency for sensorimotor and lateral visual networks correlates with domain-specific Mullen Scales in 1-year-olds, suggesting the behavioral significance of the BOLD signal frequency during infancy. Findings from this study shed light into early functional brain development and provide a new perspective for future searches for functional developmental abnormalities.

Functional Network Development During the First Year: Relative Sequence and Socioeconomic Correlations.

The first postnatal year is characterized by the most dramatic functional network development of the human lifespan. Yet, the relative sequence of the maturation of different networks and the impact of socioeconomic status (SES) on their development during this critical period remains poorly characterized. Leveraging a large, normally developing infant sample with multiple longitudinal resting-state functional magnetic resonance imaging scans during the first year (N = 65, scanned every 3 months), we aimed to delineate the relative maturation sequence of 9 key brain functional networks and examine their SES correlations. Our results revealed a maturation sequence from primary sensorimotor/auditory to visual to attention/default-mode, and finally to executive control networks. Network-specific critical growth periods were also identified. Finally, marginally significant positive SES-brain correlations were observed at 6 months of age for both the sensorimotor and default-mode networks, indicating interesting SES effects on functional brain maturation. To the best of our knowledge, this is the first study delineating detailed longitudinal growth trajectories of all major functional networks during the first year of life and their SES correlations. Insights from this study not only improve our understanding of early brain development, but may also inform the critical periods for SES expression during infancy.

Development of human brain cortical network architecture during infancy.

The brain's mature functional network architecture has been extensively studied but the early emergence of the brain's network organization remains largely unknown. In this study, leveraging a large sample (143 subjects) with longitudinal rsfMRI scans (333 datasets), we aimed to characterize the important developmental process of the brain's functional network architecture during the first 2 years of life. Based on spatial independent component analysis and longitudinal linear mixed effect modeling, our results unveiled the detailed topology and growth trajectories of nine cortical functional networks. Within networks, our findings clearly separated the brains networks into two categories: primary networks were topologically adult-like in neonates while higher-order networks were topologically incomplete and isolated in neonates but demonstrated consistent synchronization during the first 2 years of life (connectivity increases 0.13-0.35). Between networks, our results demonstrated both network-level connectivity decreases (-0.02 to -0.64) and increases (0.05-0.18) but decreasing connections (n = 14) dominated increasing ones (n = 5). Finally, significant sex differences were observed with boys demonstrating faster network-level connectivity increases among the two frontoparietal networks (growth rate was 1.63e-4 per day for girls and 2.69e-4 per day for boys, p < 1e-4). Overall, our study delineated the development of the whole brain functional architecture during the first 2 years of life featuring significant changes of both within- and between-network interactions.

Intersubject variability of and genetic effects on the brain's functional connectivity during infancy.

Infancy is a period featuring a high level of intersubject variability but the brain basis for such variability and the potential genetic/environmental contributions remain largely unexplored. The assessment of the brain's functional connectivity during infancy by the resting state functional magnetic resonance imaging (rsfMRI) technique (Biswal et al., 1995) provides a unique means to probe the brain basis of intersubject variability during infancy. In this study, an unusually large typically developing human infant sample including 58 singletons, 132 dizygotic twins, and 98 monozygotic twins with rsfMRI scans during the first 2 years of life was recruited to delineate the spatial and temporal developmental patterns of both the intersubject variability of and genetic effects on the brain's functional connectivity. Through systematic voxelwise functional connectivity analyses, our results revealed that the intersubject variability at birth features lower variability in primary functional areas but higher values in association areas. Although the relative pattern remains largely consistent, the magnitude of intersubject variability undergoes an interesting U-shaped growth during the first 2 years of life. Overall, the intersubject variability patterns during infancy show both adult-like and infant-specific characteristics (Mueller et al., 2013). On the other hand, age-dependent genetic effects were observed showing significant but bidirectional relationships with intersubject variability. The temporal and spatial patterns of the intersubject variability of and genetic contributions to the brain's functional connectivity documented in this study shed light on the largely uncharted functional development of the brain during infancy.

Development of thalamocortical connectivity during infancy and its cognitive correlations.

Although commonly viewed as a sensory information relay center, the thalamus has been increasingly recognized as an essential node in various higher-order cognitive circuits, and the underlying thalamocortical interaction mechanism has attracted increasing scientific interest. However, the development of thalamocortical connections and how such development relates to cognitive processes during the earliest stages of life remain largely unknown. Leveraging a large human pediatric sample (N = 143) with longitudinal resting-state fMRI scans and cognitive data collected during the first 2 years of life, we aimed to characterize the age-dependent development of thalamocortical connectivity patterns by examining the functional relationship between the thalamus and nine cortical functional networks and determine the correlation between thalamocortical connectivity and cognitive performance at ages 1 and 2 years. Our results revealed that the thalamus-sensorimotor and thalamus-salience connectivity networks were already present in neonates, whereas the thalamus-medial visual and thalamus-default mode network connectivity emerged later, at 1 year of age. More importantly, brain-behavior analyses based on the Mullen Early Learning Composite Score and visual-spatial working memory performance measured at 1 and 2 years of age highlighted significant correlations with the thalamus-salience network connectivity. These results provide new insights into the understudied early functional brain development process and shed light on the behavioral importance of the emerging thalamocortical connectivity during infancy.

TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases.

Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.

Rate of Chiari I malformation in children of mothers with depression with and without prenatal SSRI exposure.

Selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed to pregnant women. Therefore, research on in utero exposure to SSRIs can be helpful in informing patients and clinicians. The aim of this retrospective two-cohort study was to determine whether there is a statistically significant increase in Chiari I malformations (CIM) in children exposed to SSRIs during pregnancy. A total of 33 children whose mothers received a diagnosis of depression and took SSRIs during pregnancy (SSRI-exposed cohort) were matched to 66 children with no history of maternal depression and no SSRI exposure. In addition, 30 children whose mothers received a diagnosis of depression, but did not receive antidepressants during pregnancy (history of maternal depression cohort), were matched to 60 children with no history of maternal depression and no SSRI exposure. Main outcome was presence/absence of CIM on MRI scans at 1 and/or 2 years of age. Scans were reviewed by two independent neuroradiologists who were blind to exposure status. The SSRI-exposed children were significantly more likely to be classified as CIM than comparison children with no history of maternal depression and no SSRI exposure (18% vs 2%, p=0.003, OR estimate 10.32, 95% Wald confidence limits 2.04-102.46). Duration of SSRI exposure, SSRI exposure at conception, and family history of depression increased the risk. The history of maternal depression cohort did not differ from comparison children with no history of maternal depression and no SSRI exposure in occurrence of CIM (7% vs 5%, p=0.75, OR estimate 1.44, 95% Wald confidence limits 0.23-7.85). Replication is needed, as is additional research to clarify whether SSRIs directly impact risk for CIM or whether this relationship is mediated by severity of depressive symptoms during pregnancy. We would discourage clinicians from altering their prescribing practices until such research is available.