Animal studies suggest that prenatal alcohol exposure affects DNA methylation through antagonistic effects on methyl donors, such as folate, and via long-lasting changes in gene expression . Preliminary evidence from studies of children with fetal alcohol spectrum disorder show genome-wide differences in DNA methylation . Further research is required to examine epigenetic markers and their role in adverse outcomes among exposed youths; DNA methylation or other epigenetic markers could potentially provide objective indicators of prenatal alcohol exposure. Limitations of our study include potential maternal under reporting of alcohol use during pregnancy, imprecise retrospective data on the timing, amount, and frequency of alcohol exposure, and absence of data on trimester-specific alcohol exposure. The effects of under reporting by mothers who indicated alcohol use during pregnancy may have inflated the observed associations, while under reporting by mothers who indicated no alcohol use when they did in fact consume alcohol would have attenuated the associations toward the null. Furthermore, data were not available on mothers who regularly consumed less than a full unit of alcohol. Therefore, youths exposed to this pattern of drinking would have been included in the unexposed group, potentially diluting outcome effects. Despite the large sample size, there were relatively few cases of youths exposed to stable light drinking throughout pregnancy, and too few cases of stable heavier drinking or increased consumption throughout pregnancy, to examine the impact on offspring. There is a larger body of existing evidence based on the consequences of heavier alcohol exposure . The small sample size of youths exposed to light, stable drinking throughout pregnancy resulted in wider variance in outcome measures and may underestimate the true impact. Other notable explanatory variables of early life that may influence the observed associations between prenatal alcohol exposure and neurobehavioral outcomes include childhood adversity and quality of parental care. These variables may contribute to mediating effects of neurodevelopment and possible epigenetic modifications .

The baseline ABCD Study protocol did not capture these variables,vertical growing system although future waves will. Longitudinal analyses of this cohort should consider these variables as possible confounding factors. In addition, we did not examine the effect of preconception paternal alcohol exposure on preadolescent brain structure, and this should be explored in future studies. In conclusion, relatively light levels of prenatal alcohol exposure were associated with small yet significantly greater psychological and behavioral problems, including internalizing and externalizing psychopathology, attention deficits, and impulsiveness. These outcomes were linked to differences in cerebral and regional brain volume and regional surface area among exposed youths ages 9 to 10 years. Examination of dose-dependent relationships and light alcohol exposure patterns during pregnancy shows that children with even the lowest levels of exposure demonstrate poorer psychological and behavioral outcomes as they enter adolescence. Associations preceded offspring alcohol use and were robust to the inclusion of potential confounding factors and during stringent demographic matching procedures, increasing the plausibility of the findings. Women should continue to be advised to abstain from alcohol consumption from conception throughout pregnancy.The opioid crisis in the United States continues to worsen, with the number of opioid related deaths continuing to rise. Increases in deaths have come in multiple waves. The first was overdoses related primarily to prescription opioid pills; the second was driven by heroin-related overdoses; and the third has been driven by overdoses due to use of illicitly manufactured fentanyl and its analogs . Deaths related to synthetic opioids other than methadone, primarily fentanyl and its analogs, have recently increased from 9,580 in 2015 to 36,359 in 2019 , and provisional counts from 2020 suggest that the number has continued to increase . Given that the opioid crisis has continued to shift, it is important for research to continue to examine trends related to fentanyl use and overdose in order to most effectively inform prevention and harm reduction efforts. Centers for Disease Control and Prevention National Vital Statistics Systems mortality data have been the official source of information on opioid-related deaths in the US; however, results are typically lagged by about nine months . These data also tend to lack extensive information on characteristics or circumstances of overdoses, and information regarding nonfatal overdoses is not collected. In light of these limitations, alternate sources of national data could help further inform researchers and the public regarding characteristics of the ever-shifting opioid crisis which is currently driven by fentanyl use.

Even though reports of fatal fentanyl exposures are exponentially higher via NVSS mortality data as these reports are believed to count all or almost all related deaths in the US , we believe Poison Control data can help complement this information. Specifically, Poison Control data are uploaded in almost real time and therefore, depending on data availability, they can be used as an informative source for surveillance . National Poison Control also collects more extensive data on circumstances of exposures , and the majority of National Poison Control data are cases involving nonfatal overdoses – events that are currently lacking data at the national level. Therefore, National Poison Control data can elucidate risk factors for severity of fentanyl exposure outcomes, and determine how severity of outcomes and other circumstances of use shift over time. In this analysis, we examine trends in characteristics of fentanyl exposures in the US using National Poison Control data and we also delineate correlates of cases experiencing major adverse effects or death. We intend for these analyses not only to complement national mortality data but also to inform prevention and harm reduction efforts as the opioid crisis continues to shift.This study is based on a collaboration through the National Institute on Drug “Abuse” National Drug Early Warning System with the Researched “Abuse” Diversion and Addiction-Related Surveillance System. Poison Control data were obtained via the RADARS System Poison Center Program. Participating Poison Control Centers provided all cases involving pre-identified Micromedex codes to RADARS System staff who then reviewed select cases for accuracy. Poison Control provides treatment advice to the public and to healthcare staff treating people with suspected poisonings involving drugs, chemicals, and plants. Information about the patient and poisoning circumstances are recorded by individual PCCs as per standards set by the American Association of Poison Control Centers and stored in an electronic database overseen by the National Poison Data System. RADARS System obtained data on poisonings reported to involve fentanyl between January 2015 and December 2021.

Data were available from PCCs in all US states other than Utah prior to 2017 and North Carolina . With respect to patient characteristics, age and sex of the patient were obtained by PCC staff from the caller to the poison center, which may be the patient, health care provider, or other contact. With regard to characteristics of reported exposures, PCCs obtained information on the reason or intention for exposure, whether other drugs were co-used, the route of administration, the management site, and severity of the outcome from the caller. Reasons for use included substance “abuse,” substance “misuse,” suspected suicide attempt, therapeutic error, and various other categories of intentional and unintentional exposure. Unintentional exposure does not involve intentional use of another drug and typically refers to exposure among children. “Abuse” was defined by PCC as exposure resulting from intentional improper or incorrect use of a drug in which the patient was attempting to acquire a high,how to dry cannabis a euphoric effect, or some other psychotropic effect . “Misuse” was defined by PCC as intentional improper or incorrect, or otherwise non-medical use but for reasons other than acquiring a psychotropic effect. Information on reason was collected by specialists in poison information from PCC contacts and reviewed by RADARS System staff. SPIs are instructed to determine whether the results were due to a purposeful action or not . Based on coding guidelines provided by the AAPCC , they select the most appropriate reason for use within these categories. SPIs are instructed to record the rationale for this selection in case notes which are reviewed by RADARS System staff. In instances in which the patient is not conscious, this may impact the ability to obtain this information or create a bias due to reliance on other persons reporting. Routes of administration included ingestion, dermal administration, injection, inhalation, and other method. It cannot be determined, however, whether inhalation referred to insufflation or smoking. Patients were able to report multiple routes. Co-drug use was also queried, and we focused on reported co-use of alcohol, cannabis, cocaine, methamphetamine, gabapentin, benzodiazepines, and prescription opioids . Drug use was based on self-report and toxicology test results were considered when available. All information recorded by PCC staff was reviewed for accuracy by trained RADARS System staff. Management site was the site in which the call about the exposure to the PCC was made, and this was coded as taking place at a hospital center, on site , or patient referral. Finally, medical outcome was defined by PCC staff as none, mild, moderate, major, or death . Mild effects were defined as minimally bothersome effects, moderate effects were defined as more pronounced or prolonged effects, and major effects were defined as life-threatening or permanently disabling effects.

Deaths indicate that the patient was believed to have died in relation to use of the drug. Specifically, exposure related death was either directly determined by PCC staff involved with case management, or from death reports obtained from a medical examiner or other source . In the latter case, an AAPCC faculty review team then judged whether deaths were in fact likely responsible or at least contributory regarding the reported exposure . First, we examined trends in characteristics of fentanyl exposures. We described the prevalence of characteristics of fentanyl exposures within each separate year and then calculated absolute and relative changes in prevalence between 2015 and 2021. We also estimated whether there were changes in the proportion of each category of each covariate by time by examining whether there were linear, quadratic, or cubic trends using logistic regression. Next, we examined correlates of exposures resulting in a major effect or death. Covariates were fit into a multi-variable generalized linear model using Poisson and log link to estimate adjusted prevalence ratios for each covariate. We imputed missing data for independent variables in the multi-variable model. Multiple imputation was implemented via chained equations to handle missingness; predictors included all variables in the case complete model. We imputed 10 datasets for the multi-variable model and combined results using Rubin’s Rules . We also conducted sensitivity tests in which we repeated all analyses excluding cases reported from Connecticut. This was done because beginning in 2018, Connecticut became the only state to mandate emergency medical service providers suspecting fentanyl overdoses to report such cases to local poison control . All statistics were conducted using Stata SE 17 . This secondary analysis was exempt from review by New York University Langone Medical Center’s institutional review board. In this analysis of fatal and nonfatal fentanyl-related exposures reported to PCCs in the US, we detected significant shifts in characteristics of cases between 2015 and 2021. We also determined correlates of exposures resulting in major adverse effects or death. There were many shifts in proportion of various age groups exposed across time. Exposures among individuals in all age groups between age 13 and 39 increased in proportion over time, especially adolescents . We also determined that children, adolescents, and adults ages 50–69 were at higher risk for experiencing a major effect or death, suggesting these age groups are at particularly high risk for experiencing morbidity after exposure. The finding about increased exposures among children and adolescents is relatively unique. Although previous studies of mortality related to synthetic opioids suggest that there were increases among all age groups from 2011 through 2016, with a 93.9% increase among those age 15–24, increases were larger among those aged 35–44 and 25–34 . As such, our findings regarding children and adolescents being at increased risk for more severe outcomes may require more focus. Also, with respect to patient characteristics, the proportion of exposures increased among males. These results corroborate mortality data which suggests that since 2013, deaths related to use of synthetic opioids have increased at a faster rate then for females . In fact, in 2018, the rate of males who died from synthetic opioids was 14.2 per 100,000 compared to 5.5 per 100,000 females .