Prenatal Substance Exposure

Acoustic Cry Analyzer for the Diagnosis of Infants Suffering Withdrawal Due To Prenatal Opioid Exposure
The current national opioid epidemic has called for more objective measures of Neonatal Abstinence Syndrome (NAS), thewithdrawal that occurs in newborn infants due to the abrupt discontinuation of prenatal exposure to opiates such as prescription pain medication. Current methods to diagnose NAS rely heavily on cry characteristics (e.g. pitch, amount of crying) but are highly subjective and could lead to the misdiagnosis of NAS and poor or inappropriate treatment. We have developed an automated, computerized Infant Cry Analyzer (ICA) that quantifies the acoustic characteristics of infant cries. This system provides a reliable, objective measure of the acoustical properties of the cry necessary for the accurate diagnosis and clinical management of NAS. Our objective is to quantify the acoustic characteristics of cries of infants with NAS. This proof-of-concept project will enable us to collect data that would attract potential investors in the development of an automated, hand held "iPhone-like" device. Such a device would provide a digital readout indicative of whether or not the infant's cry is symptomatic of NAS. This information can then be used to provide a more accurate diagnosis of NAS, thereby reducing the likelihood of misdiagnosis, and improve the treatment and management of these infants. Primary Investigators: Barry Lester PhD, Stephen Sheinkopf PhD, Harvey Silverman PhD. 

Developmental Impact of Prenatal Exposure to Methamphetamine and Early Adversity on Children  
The rapidly escalating abuse of methamphetamine (METH) in the United States places a sense of urgency on understanding the consequences of METH use during pregnancy for the developing child. To our knowledge, our IDEAL (Infant Development Environment and Lifestyle) study is the only prospective longitudinal NIH study of prenatal METH exposure and child outcome.  204 exposed and 208 matched comparison children were recruited at birth from diverse populations in Iowa, Oklahoma, California and Hawaii where METH use is prevalent.  Children were evaluated at birth to age 7 years for infant neurobehavioral deficits (NNNS) and acoustic cry parameters, mother-infant attachment, cortisol reactivity, cognitive and motor development, behavior problems, school readiness and executive function.  Also measured were psychosocial risk factors (e. g, poverty, out of home placement, maternal psychiatric status, continued substance abuse in the home) to determine how the effects of prenatal METH exposure are affected for early adversity. There are over 30 publications from the IDEAL study. Primary Investigators: Barry Lester PhDLinda LaGasse PhD.

Epigenetics in Children with Prenatal Exposure to Methamphetamine
Children with prenatal exposure to methamphetamine are at risk for poor developmental outcome due to the combination of the drug effects and environmental adversity.  In this 10-year follow up of a birth cohort from the Infant Development and Lifestyle Study (IDEAL), we are studying how prenatal methamphetamine exposure and environmental adversity result in epigenetic changes that in turn affect cognitive and behavioral outcome. Primary Investigators: Barry Lester PhD, Linda LaGasse PhD.

Establishing Risk in Neonatal Abstinence Syndrome
The purpose of this research study is to find better ways to treat and diagnose infants with Neonatal Abstinence Syndrome (NAS) and improve long-term outcome. Certain genetic markers in adults who need narcotics to control pain or withdrawal are associated with more severe withdrawal and need for more medicine to control symptoms. This is research study is designed to find out if this is also true in babies, so doctors will know which infants are at highest risk for complications from NAS. Additionally, excessive crying and a high pitch cry are a sign and symptom of NAS. In this study we will investigate both genetic markers and cry acoustics in babies exposed to narcotics during pregnancy. Primary Investigator: Barry Lester PhD.
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Fetal and Neonatal Neurobehavior and Prenatal Antidepressant Exposure: Outcomes Through Early Childhood
Approximately 600,000 infants born each year are exposed to maternal depression. At least 30% of those infants will also be exposed to psychotropic medication. Fetal exposure during pregnancy to maternal depression and the medications to treat the disorder have been associated with neurobehavioral differences in infants. It has been suggested that these differences are transient and it is not known if they are related to the mother's depression or the medication used to treat the depression. This study has been following a group of children their families from the time before birth through age 7 to examine the effects of prenatal antidepressant exposure and untreated maternal depression on sleep, neurobiological rhythms, and socio-emotional development with the goals of identifying guidelines for the treatment of depression during pregnancy and biomarkers for developmental psychopathology. We are in the final year of this project and are currently examining the role of maternal MDD and prenatal SRI exposure on child sensory-motor integration, gross and fine motor control (kinematics), temperament, behavioral and emotional development, and sleep state with circadian biomarkers (urinary melatonin sulfate levels) related to psychiatric symptoms. We are also identifying potential epigenetic markers associated with these effects. The rationale for the proposed research is that once we know how early SRI exposure affects these key areas related to serotonin function, we will be able to identify specific mechanistic pathways, including epigenetic targets and biomarkers, for psychopathology. The expected outcomes will have a positive impact because they will lead to informed risk-benefit decision-making for pregnant women with MDD and provide new preventive and therapeutic targets for psychopathology in children. This will further translate into enormous reductions in overall costs due to the social and functional disability that may result from such conditions. Primary Investigators: Amy Salisbury PhD

Fetal Behavior, Brain, and Stress Response: Ultrasound Markers of Maternal Smoking
Maternal smoking during pregnancy is associated with morbidity and mortality in infants and behavioral deficits in infants and older children. Despite pervasive sanctions against smoking during pregnancy, 13-30% of infants are born exposed. This study provides a novel approach to mothers to observe in real-time, pre-birth neurobehavioral and neural markers of risk from maternal smoking using 2 and 3-dimensional fetal ultrasound. Using an approach pioneered by Dr. Salisbury (2D ultrasound combined with fetal actocardiography), our preliminary work revealed effects of maternal smoking on fetal neurobehavioral deficits and altered stress response during third trimester. However, fetal developmental trajectories leading to third trimester deficits are not known. Further, although structural brain deficits have been proposed as a key candidate mechanism underlying links between maternal smoking and offspring neurobehavioral deficits, no studies have integrated neural and behavioral markers of risk from maternal smoking. Our goals are to determine effects of maternal smoking on: 1) trajectories of fetal neurobehavioral deficits, 2) alterations in fetal stress response, and 3) volume decrements in neural and neuroendocrine structures over pregnancy. We will then test the proposal that trajectories of fetal neuro-behavioral and neural markers of risk predict infant neurobehavioral deficits and stress response, leading to discovery of mechanisms of maternal smoking in real-time during pregnancy, new pre-birth markers of risk that could improve clinical care for pregnant smokers and other high-risk pregnancies. Primary Investigators: Laura Stroud, PhD, Amy Salisbury PhD.

Kinematics Analysis in Children with Prenatal Exposure to SSRIs 
Kinematic analysis of fine motor control in 3- and 5-year olds is part of the longitudinal study of prenatal serotonin reuptake inhibitors (SRIs) and postnatal development. Kinematic analysis measures how well the reach was executed including movement time, smoothness, velocity peak, and acceleration. We manipulate visual information to examine the components of motor control in two ways: the child can see the target object but cannot see their hand; the child cannot see either the object or the hand (reaching in the dark), which requires using memory to organize the reach and grasp. New evidence has shown that prenatal SRI exposure may compromise fine motor control. We have developed an innovative protocol and are currently evaluating participants.Primary Investigators: Linda LaGasse PhD, Amy Salisbury PhD.

Maternal Lifestyle Study
The Maternal Lifestyle Study (MLS) is the largest of the NIH longitudinal studies of children with prenatal cocaine exposure.  MLS is a multi-site observational study of the long term effects of in-utero exposure to cocaine on child development.  The study included 25 data collection visits (birth to age 16 years) in the birth hospital, study clinic, home, and school.  Neurobehavior evaluation (NNNS) and acoustic cry analysis were conducted at the 1-month visit. Quality of attachment was conducted at 18 and 36 months.  Heart rate recording occurred during child activity in the study clinic.  Cortisol reactivity during the stressful Trier Task and diurnal cortisol pattern both showed a blunted response in cocaine exposed children, suggesting chronic stress in these children’s lives.  Cocaine exposed children are likely to live in adverse circumstances that may increase the likelihood of behavior problems leading to poor executive function and school achievement, psychopathology, delinquency, early sex and drug use.  MLS has published over 75 publications. Primary Investigators:  Barry Lester PhD, Linda LaGasse PhD.

The MLS data set has been submitted for public access to the National Addiction and HIV Data Archive Program, Inter-University Consortium for Political and Social Research (University of Michigan).  The URL is

Of Mice and Methylation
Psychotropic drugs (SRIs) are often used to treat maternal depression during depression. These drugs can affect the infant and perhaps have negative long-term consequences.  Translational research is often used to study mechanisms that cannot be studied in humans. In this study we are developing a mouse model of prenatal SSRI exposure to compare with human infant data to study epigenetic mechanisms that may be responsible for the effects of these drugs on newborn neurobehavior. Primary Investigators: Kevin Bath PhD, Barry Lester PhD.

Prenatal Marijuana: Impact on Infant Neurobehavior, Stress, & Epigenetic Mechanisms
Examine potential fetal and newborn outcomes related to maternal marijuana use in pregancy. This study is 
funded by the National Institute on Drug Abuse, NIH. Principal Investigator: Dr. Laura Storud, Co-Investigator: Amy Salisbury, PhD.

The Environmental Influences on Child Health Outcomes (ECHO) Neonatal Opioid Withdrawal Syndrome (NOWS) Program
Opioid use during pregnancy is a national epidemic resulting in an unprecedented increase in the incidence of babies born with Neonatal Opioid Withdrawal Syndrome (NOWS) or Neonatal Abstinence Syndrome (NAS). The purpose of the ECHO NOWS initiative is to study associations between prenatal opioid and other exposures and child outcome including NOWS. The ECHO NOWS initiative has two arms. One arm supports activities within ECHO's Cohorts. While the initial intervention work will likely focus primarily on NOWS in the nursery, the Cohorts can take a broader view of the maternal-child NOWS epidemic. The overarching goals are to inform the extent to which exposure to opioids in pregnancy affects child health outcomes, and to identify potential leverage points for policy, program, or practice responses. To this end, the ECHO NOWS Sub-Group was formed to: 1) analyze extant ECHO data and data elements specific to prenatal opioid exposure, including NOWS and 2) develop new data elements to include in the ECHO-wide data collection protocol specific to prenatal opioid exposure, including NOWS.

The second arm supports a partnership among ECHO's IDeA States Pediatric Clinical Trials Network (ISPCTN) and the Neonatal Research Network of NICHD. The ISPCTN can play a pivotal national role, given the geographical overlap in burden of NOWS and IDeA States, and the interest of ISPCTN investigators and collaborators. The aims are 1.) to get a "lay of the land" across ISPCTN in terms of burden of NOWS, capacity for ISPCTN institutions to respond, and the infrastructure of surrounding health systems to mount a response, and 2.) for ISPCTN to work alongside the Neonatal Research Network to develop a protocol for a clinical trial, which could take the form, say, of comparative effectiveness of drug A v. B, non-pharmacologic interventions, guideline implementation, or other types of interventions. 

Congress, the White House, the Department of Health and Human Services, and NIH leadership all emphasize responding to the opioid epidemic as one of the major health challenges of our time. Given the dearth of knowledge on long-term outcomes of exposure to opioids and to NOWS, and wide practice variation in clinical practice and health system support, ECHO—both the observational and intervention components—has a golden opportunity to make substantial contributions to lessening the burden of this epidemic. 

The Impact of Prenatal Methamphetamine Exposure on Children in New Zealand (NZ)
Does the impact of prenatal exposure to methamphetamine on children differ with cultural and resource differences?  The IDEAL (Infant Development Environment and Lifestyle) study in the US was replicated in NZ to compare whether differences between the societies may influence outcome in children with prenatal METH exposure.  Unlike the US, NZ has a harm reduction approach toward drug use, no mandatory reporting statutes for prenatal illicit drug use hence rare child removal, free universal health care and generous financial resources. Drug-using NZ mothers are far more likely to have prenatal care than US mothers and their infants were born  heavier and longer than US infants.  However, exposed infants in both US and NZ had a similar neurobehavioral pattern (NNNS) including under arousal, poorer quality of movement and increased stress and similar mild motor deficits from 1 to 3 years of age.  On the other hand, NZ mothers were 5 times more likely to have comorbidity between psychopathology and substance use disorder than US mothers. Ongoing analyses of academic achievement, social-emotional development and behavioral problems from 5 -7 years may be more sensitive to culture and resources as well as early adversity. Primary Investigators: Linda LaGasse PhD, Barry Lester, PhD.

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