Christina Chambers - US grants

DESCRIPTION (provided by applicant): Defining the range of expression, risk factors for, and incidence of FASD in children born to women who drink varying amounts of alcohol during pregnancy is of vital importance in terms of prevention, intervention and treatment. The proposed study entails a collaboration with the Moscow Region Ministry of Health to screen 26,000 pregnant women over two years. From these, 640 moderate to heavy drinkers and 640 controls will be selected for longitudinal follow-up including standardized physical exams and neurobehavioral testing of infants through twelve months of age. The specific aims of the project are: 1) To measure the birth prevalence and range of alcohol-related physical features and neurobehavioral impairment among children born to pregnant women in the Moscow Region who report consuming moderate to heavy amounts of alcohol by utilizing methods designed to permit earlier diagnosis of alcohol-related effects, and 2) To evaluate the contribution of maternal nutritional factors to increased risk for prenatal growth deficiency, neurobehavioral impairment, and alcohol-related physical features in infants prenatally exposed to moderate to heavy amounts of alcohol by conducting a randomized trial of a micronutrient supplementation intervention and measuring micronutrient levels in maternal blood. The proposed study will contribute to a better understanding of the incidence and range of FASD based on early diagnosis in a cross-cultural environment, and will for the first time specifically test a nutritional intervention that may have widespread applicability should undernutrition prove to be a modifiable risk factor for FASD.

fetal alcohol syndrome; vitamin deficiency; disease /disorder proneness /risk; mother /embryo /fetus nutrition; alcoholism /alcohol abuse; outcomes research; women's health; dietary mineral; maternal behavior; embryo /fetus toxicology; clinical research; human pregnant subject; human subject; nutrition related tag;

DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorders (FASD), first described in the U.S. in 1973 by Jones and Smith, encompasses a pattern of structural abnormalities, growth deficiency, and neurobehavioral impairment that occurs in the offspring of women who consume moderate to heavy amounts of alcohol in pregnancy. FASD is thought to represent the leading known preventable causes of neurobehavioral impairment in the U.S. and perhaps throughout the world. The proposed study offers the opportunity within the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) consortium of projects to describe the spectrum of alcoholrelated effects, to identify risk factors that are antecedent to pregnancy outcome, to test within-pregnancy interventions, and also to test methods that will allow for earlier identification of alcohol-related birth outcomes. Specifically, the proposed research will utilize a prospective cohort study design involving pregnant women and their offspring recruited in Russia and Ukraine to address major gaps in knowledge about FASD by accomplishing the following specific aims: 1) to more fully delineate the complete range of expression of FASD in relation to specific quantities, patterns and gestational timing of alcohol exposure, and to evaluate the sensitivity of methods for earlier recognition of affected children;2) to assess the contribution of maternal nutritional status in relation to physical and neurobehavioral outcomes associated with prenatal alcohol exposure, and to test the benefit of maternal second and third trimester supplementation with multinutrients with or without choline with respect to risk for FASD in the offspring;and 3) in collaboration with other CIFASD investigators, to provide a well-characterized sample of mothers/children with and without prenatal exposure to alcohol for testing of alternative and earlier methods of identifying affected children, including prenatal ultrasound and post-natal 3D facial imaging. The proposed research has public health relevance from the standpoint of providing an improved estimate of the magnitude and scope of alcoholrelated developmental problems in the context of specific quantities and patterns of prenatal alcohol exposure using standardized methods for assessment, and from the standpoint of developing and validating critically necessary clinical methods for improved and early recognition of affected children and testing the potential benefit of a reasonably applied prenatal intervention that may help ameliorate negative outcomes.

DESCRIPTION (provided by applicant): We propose to establish an estimate for the prevalence of FASD in a large, diverse and multicultural U.S. urban setting - San Diego, California. Through an established collaboration with the San Diego Unified School District, the San Diego Regional Center for Developmental Disabilities, and the San Diego County Child Welfare Agency, we will employ methods that will specifically address the major barriers to developing accurate prevalence estimates including reliable and valid evaluation of physical characteristics in an age range when features are most easily recognizable, comprehensive assessment of neurobehavioral performance in children just entering school-age, and detailed information on prenatal alcohol exposure. We will establish a prevalence estimate of FASD including FAS, Partial FAS and ARND in the City of San Diego metropolitan area among a cross-sectional sample of children in the first grade age range in elementary school (5-7 years of age) and those children in the same age range and geographic area receiving special services for developmental disabilities or child welfare services. In addition, we will determine risk factors for FASD in this population, enhance capacity to make valid and reliable diagnoses of FASD by training new expert diagnosticians and through the use of 3D facial imaging, and promote study recruitment and retention through the implementation of an evidence-based intervention among children identified with FASD. We will assess participation bias among parents and caregivers in the school sample to determine if there is evidence of differential recruitment among those with higher levels of prenatal alcohol use. We also propose to host the Data Access and Coordinating Center for all projects included in the CoFASP consortium through the San Diego Supercomputer Center at the University of California, San Diego. PUBLIC HEALTH RELEVANCE: Accurate estimates of the incidence and prevalence of FASD in the U.S. are lacking. The prevalence of FASD is thought to be under-estimated due to a number of factors that will be addressed in the proposed study. Establishing accurate estimates of the prevalence of FASD in representative regions of the U.S. population is critical in order to develop a better understanding of the public health impact of this disorder as well as the potential benefits of successful prevention.

DESCRIPTION (provided by applicant): Fetal alcohol spectrum disorders (FASD) are thought to be the most common developmental disabilities worldwide, and one of the few developmental disorders that are known to be completely preventable. While much research has focused on the dysmorphological and neurological features of fetal alcohol spectrum disorders (FASD), there is a critical gap in the literature with regard to our understanding of the nutritional and immunological mechanisms whereby postnatal growth and performance deficits in children affected by alcohol are initiated and subsequently persist throughout childhood, and therefore might be targets for postnatal intervention. Based on preliminary data from an ongoing clinical trial in Ukraine, conducted in a sample of moderate to heavy alcohol-consuming pregnant women, a multimicronutrient supplementation (multiple-vitamin-mineral supplement with or without additional choline) given during pregnancy is associated with a marked reduction of alcohol-related growth and neurocognitive deficits in infants at 6 and 12 months of age. These promising initial findings could have worldwide public health impact if demonstrated to persist. The primary goal of the current application is to investigate the persistence of the beneficial effects of multimicronutrient supplementation on growth and development through preschool age in an established longitudinal sample of children in Ukraine. Secondary goals of this application are to evaluate postnatal factors, including nutritional status of the child and marker of immune function and oxidative stress, that may contribute to persistent deficits among alcohol-exposed children in the context of prenatal nutritional factors. The proposed study will build on the strengths of an established Ukrainian cohort of well- characterized children, now between 2 and 5 years of age: a) to assess the impact of known prenatal alcohol exposure, with or without a past prenatal nutritional intervention, on the child's growth and neurobehavioral function through 5 years of age, and b) to determine the antecedents of an alcohol-affected child's postnatal nutritional and immunologic status and the contribution of this postnatal environment to persistent neurobehavioral and growth deficits.

DESCRIPTION (provided by applicant): It is estimated that Fetal Alcohol Spectrum Disorders (FASD) is the most common neurodevelopmental disability among children throughout the world. Furthering our understanding of the factors that potentially modify risk for FASD, continue to be critical gaps in research that could drive prevention and intervention strategies throughout the world. A longitudinal cohort sample has been established in Ukraine during the current funding period with detailed documentation of prenatal alcohol exposure, maternal nutritional status, and FASD outcomes. In this same sample a multimicronutrient supplement intervention trial has been implemented. During the renewal period, we propose to examine the persistence of and/or the novel manifestation of beneficial neurobehavioral effects of the prenatal multimicronutrient intervention trial, to examine the role of postnatal child nutrition in FASD, an to explore genetic and epigenetic factors as biomarkers of maternal exposure and risk modification among alcohol consuming pregnant women.

Project Summary Accurate diagnosis and early identification of infants or children with Fetal Alcohol Spectrum Disorders (FASD) is essential to initiating early intervention leading to improved outcomes for affected children. However, children with FASD are most often not diagnosed until many years after birth. As a result, many years of appropriate and beneficial intervention or treatment are missed. Given the high prevalence of FASD in areas of the world where the disorder has been studied, earlier and more accurate recognition of children with FASD is of high public health importance. Building on the existing Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) longitudinal cohort study in Ukraine, we aim to fill this critical gap in knowledge in two ways. First, we will develop a panel of three prenatal/early infancy biomarkers that can predict FASD. These biomarkers include maternal and infant microRNA expression profile, maternal and infant cytokine expression profile, and an early infancy measure of neurobehavioral performance. Second, we will develop risk/resilience prediction models based on the developmental trajectories of children enrolled in the cohort. These models will identify the characteristics of a prenatally exposed infant/child at a given age that are predictive of the child's later growth and performance. This work will support earlier identification of affected children and can help to determine appropriate early allocation of resources for intervention and treatment to those children most likely to benefit. Furthermore, our findings may suggest novel approaches to biological and environmental targets for treatment and intervention. We will also work collaboratively with other investigators in the CIFASD Consortium to interactively address the overall goals of the Consortium in improving diagnosis and treatment of FASD.

PROJECT SUMMARY Early identification of children who are affected by prenatal exposure to alcohol, i.e., who have Fetal Alcohol Spectrum Disorders (FASD), is essential to initiating early intervention. Early interventions can take advantage of neuroplasticity in young children and thus can improve outcomes for a child with FASD. However, current methods of testing young children for neurodevelopmental impairments are limited in their effectiveness and costly to administer. As a result, many children are not recognized as having FASD and years of appropriate and beneficial intervention or treatment are missed. Given the high prevalence of FASD in areas of the world where the disorder has been studied, earlier and more accurate recognition of children with FASD is of high public health importance. Building on the existing Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) longitudinal cohort study in Ukraine, we will fill this critical gap by testing three novel, technology- based and scalable methods that can identify impairments in brain functioning in young children. These novel measures can lead to earlier, rapid, more accurate, and cost-efficient detection of neurodevelopmental disorders due to prenatal alcohol. Furthermore, the scalable methods being tested have global

Project Summary In 2015, the U.S. Food and Drug Administration (FDA) introduced the Pregnancy and Lactation Labeling Rule, a new system that removed the pregnancy letter ratings (A,B,C,D,X) from all Prescribing Information and replaced them with a narrative summary of animal and human gestational safety data and clinical considerations. Asthma is the most common potentially serious medical problem to occur during pregnancy. The revised Prescribing Information highlights a critical need for high quality human safety data to inform the use of asthma medications during pregnancy and lactation. Randomized controlled trials in this population are not sufficiently feasible to address all evidence gaps in this population. Well-designed observational studies are needed to fill evidence gaps and guide clinical decision-making during pregnancy. Progress in the care of asthma during pregnancy requires multi-stakeholder meetings to prioritize the most important evidence gaps, including individuals with a history of asthma during pregnancy, their caregivers, clinicians, professional societies, the pharmaceutical industry, patient advocacy organizations, payers, policymakers, and research methodologists. To our knowledge, these groups do not have a formal venue in which to work together to review progress in the field, identify and prioritize research activities in the discovery and delivery sciences, and develop collaborations to fill the most important evidence gaps. The overall goal of this conference is to convene relevant stakeholders to develop a research agenda regarding the safety of asthma medications during pregnancy and lactation. We will submit for peer-reviewed publication a workshop report within 12 months of the start of the project period. More importantly, this meeting will catalyze the development of a multi-stakeholder consortium.

ABSTRACT The Planning for the HEALthy Early Development Study will contribute to the design and recommended protocol for a future large-scale, multi-site research study to prospectively examine human brain, cognitive, behavioral, social and emotional development of children beginning prenatally through ages 9-10, and to determine the impact of maternal pre- and postnatal substance use on short- and long-term development of children. The Planning Study will link investigators across 6 research sites who have complementary experience and expertise in the areas that are essential to designing the study. Planning activities will be accomplished using a coordinated set of 10 Working Groups who will work collaboratively to design a sampling and recruitment strategy for a future large-scale study, to identify and recommend strategies for addressing the challenges to ethical recruitment and retention of vulnerable populations, and to develop and test a common protocol for neuroimaging, infant and child assessments, exposure assessment, biospecimen collection, and integration of novel technologies. By the end of the Planning Phase, the 6 Consortium sites will have produced and tested a recommended protocol for the future multi-site study, and will have established feasibility of carrying out the study protocol at each of the 6 linked sites.

PROJECT SUMMARY Neurodevelopmental processes are shaped by dynamic interactions between genes and environments. Maladaptive experiences early in life can alter developmental trajectories, leading to harmful and enduring developmental sequelae. Pre- and postnatal hazards include maternal substance exposure, toxicant exposures in pregnancy and early life, maternal health conditions, parental psychopathology, maltreatment, structural racism, and excessive stress. To elucidate how various environmental hazards impact child development, it is imperative that a normative template of developmental trajectories over the first 10 years of life be established based on a sufficiently large and demographically diverse sample of the US population. To accomplish this, the Healthy Brain and Child Development National Consortium study (HBCD) under the leadership and management of the HBCD National Consortium Administrative Core (HCAC) will deploy a harmonized, optimized, and innovative set of neuroimaging (MRI, EEG) measures complemented by an extensive battery of behavioral, physiological, and psychological tools, and biospecimens to understand neurodevelopmental trajectories in a sample of 7,500 mothers and infants enrolled at sites across the US. The overarching goal of the HBCD is to create a comprehensive, harmonized, and high-dimensional dataset that will characterize typical neurodevelopmental trajectories in US children and that will assess how biological and environmental exposures affect those trajectories. A special emphasis will be placed on understanding the impact of pre- and postnatal exposure to opioids, marijuana, alcohol, tobacco and/or other substances. To address these broad objectives, the HCAC will oversee study design, development of the common protocol, and monitor recruitment and retention to ensure that the sample of women enrolled includes: 1) a racially, ethnically, and socioeconomically diverse cohort that is representative of the US population; 2) pregnant woman with use of targeted substances (opioids, marijuana, alcohol, tobacco); and 3) demographically and behaviorally similar women without substance use in pregnancy to enable valid causal inferences. The HCAC will ensure study objectives are met, monitor performance, provide for training, establish and carry out decision-making and ethical policies, manage all study communications, and oversee processes for considering study modifications. In collaboration with the HBCD National Consortium Data Coordinating Center (HDCC), the HCAC will ensure that approximately annual study datasets are released to the broader scientific community. The HBCD National Consortium study will inform public policy to improve the health and development of children across the nation.

PROJECT SUMMARY The UC San Diego MPRINT CET, entitled ?Optimization of Antibiotics in Mothers and Their Breastfed Infants Using Pharmacomicrobiomic and Metabolomic Analyses?, brings together a team of highly experienced and proven collaborative investigators with leadership roles in maternal and pediatric clinical pharmacology, fundamental research methods and technologies. Across its highly integrated and synergistic components, the UCSD MPRINT CET addresses critical barriers in maternal-infant pharmacology regarding (1) the pharmacokinetics of infant exposure to maternal antibiotic treatment via breastmilk or close contact, (2) the impact of maternal antibiotic therapy or prophylaxis on establishment of the normal infant microbiome and gut metabolome, (3) potential downstream effects of such antibiotic exposure on infant immune function and hepatic cytochrome P450 drug metabolizing enzymes, and (4) the pivotal role of breast milk both as a conduit for antibiotic transfer and source of beneficial human/mammalian milk oligosaccharides (HMOs/MMOs) that may support microbiome and immune integrity in face of antibiotic stress. The successful operation and outcome of our MPRINT CET is accomplished through 3 Projects (Clinical, Basic Science and Data Science) an Administrative Core and two Technology Cores, the Milk Analytics Core (MAC) and Pharmacometrics and Analytical Chemistry Core (PACC). In the Clinical Project ?Antibiotic Treatment in Breastfeeding Mothers: Effects on Milk, Microbiome, and Infant Outcomes?, we have proven expertise and infrastructure and access to a high enrolling maternal-infant clinical cohort to study how maternal antibiotics alter breast milk composition and impact infant outcomes in clinical meaningful ways. In the Basic Science Project ?The Impact of Ampicillin and Breast Milk Oligosaccharides on the Infant Microbiome and Immune Functions?, we leverage extensive experience in mouse models of neonatal host-pathogen interactions to probe functional effects of ampicillin and MMOs on infant immune function, including a novel cross-fostering strategy with wild-type and MMO-deficient mothers. In our Data Science Project ?Impact of Maternal Antibiotics on the Breastfeeding Infant Microbiome and Metabolome?, we deploy advanced MS technology, non-invasive sampling and innovative molecular networking analytics in a cutting-edge study of the impact of breast milk antibiotic exposure on the infant microbiome, metabolome and hepatic Cyp enzymes. The MAC provides milk collection protocols and kits, near infrared spectroscopy and HPLC, HMO/MMO and nutritional composition analysis, and new assay validation expanding our MPRINT CET analytical capabilities, while the PAC develops and validates novel quantitative assays and physiologic and semi-physiologic models to describe and predict maternal and infant antibiotic PK during breastfeeding. Our Administrative Core oversees integration and performance of our research projects/cores and their milestones, connecting them to the national MPRINT CET HUB and unique training/pilot projects.

PROJECT SUMMARY Breastfeeding is the recommended primary source of nutrition for infants and has been associated with cognitive and other health benefits for the developing child. An estimated 50-80% of women take prescription medications while breastfeeding, yet only 2% of medications have adequate data for evaluating their safety when used in lactation. This represents a critical gap in knowledge resulting in many women either avoiding necessary medications or discontinuing breastfeeding. The primary barrier to determining the extent of drug passage into breast milk is collecting enough breast milk and blood samples to both quantify drug concentrations and account for inter-individual variability in drug exposure. For numerous reasons, it is often difficult for new mothers to come to study visits. In order to generate much-needed data on drug passage into breast milk, additional methods of sample collection are needed that will enable more lactating women to participate and to generate a sufficient critical mass of data to make strong recommendations on the safety of a given drug while breastfeeding. This proposal will rigorously test the central hypothesis that home collection of human milk and blood samples will be successfully validated against more traditional clinic-based collection methods for pharmacokinetic (PK) studies. Building on the infrastructure of the existing UC San Diego Human Milk Research Biorepository study and a highly qualified, multidisciplinary research team at UC San Diego and the University of Utah, we will enroll 20 breastfeeding women already prescribed either prednisone, oxycodone, sertraline, or methylphenidate, for a total of 80 women. In each medication group, 10 women will be randomly assigned to one of two cohorts. Women in Cohort 1 will present to clinic and provide a breast milk and blood sample that will be split into two aliquots. Aliquot 1 will be processed and stored under rigorous study collection conditions. Aliquot 2 will be processed and stored under mimicked home collection conditions. Storing the same sample under different conditions will allow comparison of home collection to the gold standard of clinic collection. The data collected from Cohort 1 will be combined with existing PK data from a collaborating network to build population PK models. These PK models will be used to generate model-predicted concentrations that will be compared with home-collected concentrations from Cohort 2. Women in Cohort 2 will be provided instructions and supplies for home collection of breast milk and dried blood spot samples that will be shipped to UC San Diego. Concentrations from home- collected samples will be compared to model-predicted concentrations from the PK models generated above. By successfully validating methods for home collections, the proposed research will transform the study of drug passage into breast milk by dramatically expanding the number of women who can participate, ultimately leading to an exponential increase in the number of medications for which there is adequate lactation safety data. The methods developed in this R21 proposal will be used to inform a large prospective, opportunistic trial of multiple drugs across numerous therapeutic areas and will involve collaboration with large US and European networks.

PROJECT SUMMARY Antibiotic use is common among women of reproductive potential, including lactating women. However, little is known about the transmission and pharmacokinetics of specific antibiotics in human milk, nor the effects of antibiotic treatment on milk composition and quality including nutritional components, oligosaccharide profile, and the microbiome. Establishment of the infant gut microbiome is dependent on a dynamic maternal?infant microbiota exchange during early life, which is largely facilitated via breastfeeding. It is thus critical to better understand the impact of specific antibiotics on milk composition. Furthermore, it is essential to determine how maternal antibiotic use may impact infant outcomes, including growth, development, and immune response. Building on the infrastructure of the University of California San Diego Human Milk Research Biorepository, a highly qualified, multidisciplinary research team will prospectively enroll and interview 480 maternal/infant pairs at baseline, collect milk, skin, and stool samples, and monitor ongoing breastfeeding practices and maternal use of one of four commonly used antibiotics over time. From these, we will subsequently identify 40 maternal/infant pairs with maternal uptake of target antibiotic treatment, 40 matched maternal/infant pairs without antibiotic exposure, and 20 non-lactating maternal/infant pairs with maternal uptake of a target antibiotic treatment. From these 100 pairs, we will collect additional home and maternal and infant biomarkers of exposure at 3 timepoints corresponding to antibiotic initiation, mid-course, and end-course, collect interview and medical record data, and obtain a questionnaire assessment of infant development at 12 months post-partum. Data will be used to determine the amount and pharmacokinetics of target antibiotics in breast milk samples and to test the central hypotheses that (1) milk composition, oligosaccharide, and microbiome profiles will differ between groups by antibiotic treatment status; (2) microbiome and metabolomic measures will differ in treated and untreated breastfeeding groups; and (3) antibiotics will be detectable in the stool, skin, and home environment swabs of mothers who are treated with antibiotics but are not breastfeeding. We will also explore the impact on maternal antibiotic use on infant growth and development. Findings of this study will fill a critical gap in knowledge regarding the presence of commonly used antibiotics in breast milk and the effects of antibiotic treatment on both breast milk composition and quality as well as short- and long-term infant outcomes, including growth, development, gut health, and immune response. This will inform evidence-based development of specific guidance on antibiotic use during lactation and help support advice provided by healthcare providers to breastfeeding women.