BACKGROUND:Recent interest in the screening and diagnosis of fetal alcohol spectrum disorders (FASD) by the American Psychiatric Association and the American Association of Pediatrics has highlighted the lack of empirical evidence regarding the levels and patterns of prenatal alcohol exposure (PAE) associated with clinically significant adverse effects on cognitive and behavioral function. We used benchmark dose analysis to address this issue. METHODS:Benchmark dose analyses were performed on composite cognitive function scores derived from data obtained at school age, adolescence, and early adulthood from 2227 participants from six prospective, longitudinal cohorts, whose mothers were interviewed about their alcohol and drug use during pregnancy or shortly thereafter. We compared single-predictor models based on average alcohol consumed per day during pregnancy with a two-predictor, semiparametric model based on (1) average alcohol dose per drinking occasion and (2) drinking frequency. RESULTS:Our two-predictor model showed that at lower levels of drinking frequency, a relatively high dose/occasion is required for an increased risk of poor intellectual function, whereas at higher levels of drinking frequency, a lower dose/occasion is sufficient to increase that risk. In addition, lower doses/occasion were associated with clinically meaningful adverse effects in participants born to older than to younger mothers. The single-predictor models proved less adequate because the dose/occasion for a substantial proportion of participants exposed at the benchmark doses generated by those models was too low to increase the risk of clinically significant effects. CONCLUSIONS:Given that the cognitive and behavioral deficits seen in FASD resemble those also seen in a range of other disorders, whether the patient's PAE is sufficient to increase the risk of clinically meaningful impairment is a critical element in an FASD diagnosis. Accurate diagnosis is needed to determine which patients warrant interventions that have been shown to be effective in remediating PAE-related neurobehavioral impairment.

While benchmark dose (BMD) methodology is well-established for settings with a single exposure, these methods cannot easily handle multidimensional exposures with nonlinear effects. We propose a framework for BMD analysis to characterize the joint effect of a two-dimensional exposure on a continuous outcome using a generalized additive model while adjusting for potential confounders via propensity scores. This leads to a dose-response surface which can be summarized in two dimensions by a contour plot in which combinations of exposures leading to the same expected effect are identified. In our motivating study of prenatal alcohol exposure, cognitive deficits in children are found to be associated with both the frequency of drinking as well as the amount of alcohol consumed on each drinking day during pregnancy. The general methodological framework is useful for a broad range of settings, including combinations of environmental stressors, such as chemical mixtures, and in explorations of the impact of dose rate rather than simply cumulative exposure on adverse outcomes.

BACKGROUND:Most studies of the effects of prenatal alcohol exposure (PAE) on cognitive function have assumed that the dose-response curve is linear. However, data from a few animal and human studies suggest that there may be an inflection point in the dose-response curve above which PAE effects are markedly stronger and that there may be differences associated with pattern of exposure, assessed in terms of alcohol dose per drinking occasion and drinking frequency.METHODS:We performed second-order confirmatory factor analysis on data obtained at school age, adolescence, and early adulthood from 2227 participants in six US longitudinal cohorts to derive a composite measure of cognitive function. Regression models were constructed to examine effects of PAE on cognitive function, adjusted for propensity scores. Analyses based on a single predictor (absolute alcohol (AA)/day) were compared with analyses based on two predictors (dose/occasion and drinking frequency), using (1) linear models and (2) nonparametric general additive models (GAM) that allow for both linear and nonlinear effects.RESULTS:The single-predictor GAM model showed virtually no nonlinearity in the effect of AA/day on cognitive function. However, the two-predictor GAM model revealed differential effects of maternal drinking pattern. Among offspring of infrequent drinkers, PAE effects on cognitive function were markedly stronger in those whose mothers drank more than ~3 drinks/occasion, and the effect of dose/occasion was strongest among the very frequent drinkers. Frequency of drinking did not appear to alter the PAE effect on cognitive function among participants born to mothers who limited their drinking to ~1 drink/occasion or less.CONCLUSIONS:These findings suggest that linear models based on total AA/day are appropriate for assessing whether PAE affects a given cognitive outcome. However, examination of alcohol dose/occasion and drinking frequency is needed to fully characterize the impact of different levels of alcohol intake on cognitive impairment.

This is a report from the most recent adult follow-up of the longest running cohort study of prenatal cocaine exposure (PCE), in which women were enrolled prenatally and offspring were assessed in infancy, childhood, adolescence, and young adulthood. In previous studies, PCE was linked to offspring behavior problems such as early substance use and externalizing behavior problems. The current analyses examine pathways from PCE to behavioral outcomes in offspring at the 25-year assessment. Prenatal cocaine exposure was moderate in this cohort; most women decreased or discontinued use after the first trimester. During the first and third trimesters, 38% and 11% used cocaine, respectively. This represents the most common pattern of PCE in non-treatment samples. At this phase, the adult offspring were, on average, 27.3 years old (range = 25-30), had 13.4 years of education, 83% were employed, 55% were Black, and 55% were female. Offspring who were exposed to cocaine during the first trimester were significantly more likely to use marijuana in the past year, report more arrests, and have poorer scores on a decision-making task, controlling for other prenatal substance exposure, demographic, and socioeconomic factors. In mediation analyses, there were indirect pathways from PCE to current marijuana use through early initiation of marijuana use and 21-year marijuana use, and through 15-year status offenses and 21-year marijuana use. There was also an indirect pathway from PCE to lifetime arrests through early initiation of marijuana use and 21-year Conduct Disorder, although the direct pathway from PCE to arrests also remained significant. These findings are consistent with those from previous phases and are an indication that there are detrimental associations with PCE that persist across developmental stages and into adulthood.

The association between cannabis exposure and memory function has been examined in many studies, but it remains difficult to characterize. Reported deficits differ based on a number of methodological and drug use factors. Cannabis exposure occurs in the context of variables that influence its impact on memory, including age and polysubstance use. Methodological factors such as how drug use is reported, differences in periods of abstinence, and the type of memory function assessed also influence the conclusions that can be drawn about the effects of cannabis on memory. Further, the timing, frequency, and dose of cannabis, and whether it is used acutely or chronically are important drug exposure factors associated with memory deficits and cannabis exposure. This review considers the effects of cannabis exposure on memory function from a developmental lens. We review the effects of cannabis exposure on memory following prenatal, adolescent, and adult exposures and then consider how cannabis exposure across the lifespan interacts to impact memory function.

High levels of prenatal alcohol exposure (PAE) result in significant cognitive deficits in children, but the exact nature of the dose-response relationship is less well understood. To investigate this relationship, data were assembled from six longitudinal birth cohort studies examining the effects of PAE on cognitive outcomes from early school age through adolescence. Structural equation models (SEMs) are a natural approach to consider, because of the way they conceptualise multiple observed outcomes as relating to an underlying latent variable of interest, which can then be modelled as a function of exposure and other predictors of interest. However, conventional SEMs could not be fitted in this context because slightly different outcome measures were used in the six studies. In this paper we propose a multi-group Bayesian SEM that maps the unobserved cognition variable to a broad range of observed outcomes. The relation between these variables and PAE is then examined while controlling for potential confounders via propensity score adjustment. By examining different possible dose-response functions, the proposed framework is used to investigate whether there is a threshold PAE level that results in minimal cognitive deficit.

One in four Americans have used cannabidiol (CBD) products in the past year, and use has become prevalent in many Western countries with recent deregulation from a controlled or illicit substance to an unrestricted product. CBD is also marketed to pregnant people to treat common medical conditions. However, preclinical work has linked cannabidiol exposure to embryotoxicity, as well as neuroendocrine, reproductive, and behavioral effects in offspring. No studies have examined the prevalence or correlates of CBD use among pregnant people. Demographic, medical, and psychosocial correlates of cannabidiol use were examined in the YoungMoms study, a cohort of pregnant people under the age of 22, a population that is at high risk for cannabis use during pregnancy. Few of the participants (n = 186; 75% Black or Biracial) reported use of cannabidiol during pregnancy, but one in five had tried these products. Participants who reported ever using CBD were more likely to report alcohol and other drug use prior to pregnancy, controlling for race. As the use of CBD among people of reproductive age is increasingly prevalent, more research on CBD use in pregnant human populations is needed to investigate the effects of CBD on fetal development and infant outcomes.

Although rare, esophageal atresia (EA) and/or tracheoesophageal fistula (TEF) can lead to severe morbidity and mortality. A known complication of EA and/or TEF repair is vocal fold motion impairment (VFMI).To characterize the prevalence of VFMI among repaired EA and/or TEF at a national level and to identify factors associated with in-patient mortality and common clinical endpoints in this population (tracheostomy and gastrostomy tube dependence).This is a retrospective cohort study of inpatient neonate admissions with EA and/or TEF in the 2016 Kids' Inpatient Database (KID). Patients with a history of EA and/or TEF were identified with ICD-10 codes. VFMI prevalence was assessed by observed frequencies and percentages. Clinical endpoints included gastrostomy (G-)tube placement, tracheostomy status, and inpatient mortality. Potential predictors of these three primary outcomes included cardiac anomalies, airway disorders, chromosomal anomalies, surgery within 24 h of admission, prematurity, and low birthweight (LBW). Chi-squared analysis was performed between each parameter and the primary outcomes. Significant associations (p-value<0.05) were further assessed with multivariate logistic regression.Of 1062 neonates with history of EA and/or TEF, 24 (2.3%) had VFMI. Among this population, 27 patients underwent tracheostomies and 63 required G-tubes. There was a significantly higher likelihood of tracheostomy in patients with VFMI compared to patients without (16.7% versus 2.2%; p < 0.01). After multivariate analysis, birthweight less than 1.5 kg (BW < 1.5 kg; OR = 2.5, 95% CI: 1.03–6.10), extreme prematurity (OR = 7.5, 95% CI: 2.00–28.07), cardiac anomalies (OR = 1.8, 95% CI: 1.01–3.04) and chromosomal anomalies (OR = 4.2, 95% CI: 2.39–7.44) were significantly associated with in-hospital mortality. Bronchopulmonary dysplasia (BPD; OR = 4.7, 95% CI: 1.73–12.78) and BW < 1.5 kg (OR = 2.4, 95% CI: 1.05–5.49) were significant predictors for G-tube status. For tracheostomy, BPD (OR = 15.8, 95% CI: 4.70–52.83) and subglottic stenosis (SS, OR = 11.2, 95% CI: 1.85–68.02) remained significant predictors after multivariate regression.The national prevalence of VFMI among neonates following EA and/or TEF repair was 2.3% and was associated with an increased likelihood of tracheostomy in the KID 2016. Significant predictors of in-hospital mortality were cardiac anomalies, chromosomal anomalies, extreme prematurity, and BW < 1.5 kg. BPD and SS were significant predictors of tracheostomy, and BPD and BW < 1.5 kg were significant predictors for G-tube requirements.

Purpose: Sexual minority (SM) youth have higher rates of substance use and pregnancy but are absent from the prenatal substance use literature. We modeled the impact of SM identity and syndemic factors on prenatal substance use among 14- to 21-year-olds. Methods: Pregnant people completed an online survey (n = 357). Prenatal substance use was regressed on SM identity, controlling for other syndemic factors (e.g., depressive symptoms, intimate partner violence) and household substance use. Results: Pregnant SM participants (n = 125) were primarily bisexual and were more likely to use tobacco and illicit drugs than heterosexual participants (n = 232). The association between SM identity and prenatal tobacco use was not attenuated by syndemic factors, prenatal cannabis use, or household tobacco use. Conclusion: SM people need increased support for smoking cessation to redress health inequities in tobacco use, prevent prenatal exposures to tobacco, and limit the long-term consequences of tobacco use on health.

Introduction: Many studies have examined changes in marijuana use across adolescence, but few have examined factors associated with transitions from adolescence to young adulthood. We examined prenatal exposures to alcohol and marijuana and adolescent risk and protective factors that best distinguished among abstinence, continuity, or cessation of marijuana use from 16 to 22 years. Method: Data were from the Maternal Health Practices and Child Development Project at the prenatal and 16 -and 22-year follow-up phases. The offspring were of lower socioeconomic status with an average of 12.8 years of education at 22 years. Participants' frequency and quantity of marijuana use over the past year were used to determine change in use. A discriminant analysis was applied to distinguish among the identified groups. The risk factors considered included prenatal substance exposures and age 16 demographics, behavior, and home environment. Result: Four categories of transitions were defined based on marijuana use from 16 to 22 years: non-users (n = 193), stop/decrease (n = 81), continue at same level/increase (n = 125), and initiation after the 16-year phase (n = 122). The factors that best distinguished among these groups were peers' marijuana use, delinquency, care-givers' financial strain, prenatal exposure to alcohol and marijuana, and race. Conclusion: Prenatal alcohol and marijuana exposure were significantly related to transitions of marijuana use from adolescence to young adulthood, controlling for peers' use, behavior problems, and home environment. While gestational marijuana exposure was associated with early initiation/increasing use, alcohol exposure was related to later initiation. The findings emphasize the long-term effects of prenatal exposure to alcohol and marijuana.

With the increased prevalence, potency, and acceptability of cannabis use during pregnancy, it is important to understand the developmental effects of prenatal cannabis exposure (PCE). This review discusses methodological considerations for studies of PCE, including the assessment of exposures, covariates, and outcomes, and reviews findings from prospective, longitudinal studies of PCE. There is some evidence for associations between PCE and restricted growth at birth, but not for long-term effects on growth. PCE appears to have subtle yet enduring effects on memory and achievement in children and adolescents. Despite differences in sample demographics and measurement, there are remarkably consistent effects of PCE on externalizing behaviors, such as delinquency and substance use, which persist into adulthood. Longitudinal analyses demonstrate the importance of early cannabis initiation for pathways between PCE and adult functioning, including substance use and abuse, memory deficits, and psychotic symptoms. Animal studies demonstrate direct effects on the development of the brain via activation of endogenous endocannabinoid systems. Cannabis-induced activation of the endocannabinoid system causes alterations in the release of neurotransmitters and the modulation of brain plasticity in neural pathways that underlie cognition, motivation, and behavior regulation. Future research should consider cannabis use before pregnancy, the timing and route of exposure, polysubstance exposures, and inter-generational effects.

Evidence from animal models and epidemiological studies has linked prenatal alcohol exposure (PAE) to a broad range of long-term cognitive and behavioral deficits. However, there is virtually no information in the scientific literature regarding the levels of PAE associated with an increased risk of clinically significant adverse effects. During the period from 1975-1993, several prospective longitudinal cohort studies were conducted in the U.S., in which maternal reports regarding alcohol use were obtained during pregnancy and the cognitive development of the offspring was assessed from early childhood through early adulthood. The sample sizes in these cohorts did not provide sufficient power to examine effects associated with different levels and patterns of PAE. To address this critical public health issue, we have developed a hierarchical meta-analysis to synthesize information regarding the effects of PAE on cognition, integrating data on multiple endpoints from six U.S. longitudinal cohort studies. Our approach involves estimating the dose-response coefficients for each endpoint and then pooling these correlated dose-response coefficients to obtain an estimated `global' effect of exposure on cognition. In the first stage, we use individual participant data to derive estimates of the effects of PAE by fitting regression models that adjust for potential confounding variables using propensity scores. The correlation matrix characterizing the dependence between the endpoint-specific dose-response coefficients estimated within each cohort is then run, while accommodating incomplete information on some endpoints. We also compare and discuss inferences based on the proposed approach to inferences based on a full multivariate analysis

Introduction: The goals of this study were to model maternal patterns of cannabis use from one year pre-pregnancy to 16 years postpartum and to determine if different patterns of maternal cannabis use predicted offspring substance use at age 22. Methods: Women were recruited from a prenatal clinic between 1982 and 1984. Maternal cannabis use was assessed by trained interviewers twice during pregnancy, at delivery, 8 and 18 months, 3, 6, 10, 14, and 16 years postpartum. At age 22, substance use and dependence were measured in offspring. Growth mixture models of maternal cannabis use were calculated and adult offspring substance use outcomes were regressed onto maternal cannabis trajectory classes (n = 551). Results: There were five distinct patterns of maternal cannabis use. Offspring of mothers who were chronic cannabis users were more likely to use cannabis (p < 0.001) and develop CUD (p < 0.05) than offspring whose mothers did not use cannabis. Offspring of chronic cannabis users were also more likely to be nicotine dependent by age 22 than offspring whose mothers did not use cannabis (p < 0.01) and than offspring whose mothers were decreasingly likely to use over time (p < 0.01). Conclusions: Integrated variable- and person-centered analyses revealed long-term and meaningful patterns of cannabis use and desistance. Chronic maternal cannabis use is a risk factor for regular and dependent cannabis use and for dependent tobacco use among young adult offspring. These findings have implications for maternalchild health given the increasing prevalence of cannabis use among women.

More Americans are using marijuana than in previous decades but there are concerns over its long-term impact on cognitive functioning, especially memory. The literature on marijuana use and cognitive functioning is mixed, with some studies showing recovery of functioning upon abstinence from the drug and others showing long-term effects that persist. The latter seems especially true for individuals who initiate marijuana at a younger age and engage in more chronic patterns of use. The goal of the current study is to use prospectively collected data on young adults from a prenatal cohort to determine if there is an effect of early and/or current marijuana use on young adult memory, controlling for prenatal exposure to marijuana use, childhood memory deficits, and other significant covariates of memory functioning. At the 22-year follow-up phase of the Maternal Health Practices and Child Development (MHPCD) study, 524 young adults (58% Black, 42% White, 52% female) completed the Wechsler Memory Scale-III. Multiple regression analyses and structural equation modeling were used to determine the effect of marijuana exposure during gestation, early adolescence, and young adulthood on young adult memory function. Results indicated that initiating marijuana use before age 15 placed young adults at greater risk of memory deficits, even after controlling for childhood memory and current marijuana use. First trimester marijuana exposure also indirectly predicted young adult memory function via childhood memory deficits and early initiation of marijuana. These findings highlight the risk of prenatal marijuana exposure and early initiation of marijuana for long-term memory function in adulthood.

Introduction: Daily combustible cigarette use is common among cannabis users, and dual use of cigarettes and cannabis is associated with detrimental outcomes. This study addresses gaps in the literature by examining data from the prenatal and adolescent phases of a prospective, longitudinal study to predict adult daily dual use. Methods: Young adult offspring (M age = 22.8 years, 53% female) from a prenatal cohort reported on combustible cigarette and cannabis use (N = 500, 58% Black, 42% White). Pathways to daily dual use were modeled using variables from the gestational and adolescent phases of the study including prenatal tobacco, alcohol, and cannabis exposures; ages at initiation of cigarettes and cannabis; and adolescent learning/memory, impulsivity, and behavior problems. Results: Prenatal cannabis and tobacco use were not directly linked to adult daily dual use of cannabis and tobacco. However, structural equation modeling revealed three significant indirect pathways from prenatal cigarette and cannabis exposures to adult daily dual use of cigarettes and cannabis via early cigarette initiation, early cannabis initiation, and adolescent behavior problems. Conclusions: This study identified pathways from prenatal cannabis and tobacco exposure to adult daily dual use, in addition to clarifying adolescent outcomes that may be part of the pathways. In a climate of growing acceptance of cannabis use and increasing legalization of recreational use, these findings serve as a warning that early exposure to cannabis may have an important role in shaping long-term dual use of tobacco and cannabis.

BackgroundPrior research on prenatal cocaine exposure (PCE) indicates that exposed children experience behavioral dysregulation resulting in risky adolescent behavior including earlier initiation of cannabis use and sexual intercourse. The goal of this study was to examine the long-term effects of PCE on adult sexual behavior.MethodsThis is a prospective cohort study of the association between PCE and risky adult sexual behavior and sexually transmitted infections (STIs) in 202 young adults (mean age = 27, SD = 0.98 years). The sample was 55% female, 46% White, and 54% Black. Data from the prenatal, childhood, and adolescent phases of the study were used to delineate pathways from PCE to adult sexual behavior.ResultsThe most common risky sexual behavior was having sex while drunk or high (63%). One-third of the sample reported that they “almost always” had sex while drunk or high. We found evidence for an indirect pathway from PCE to adult sex while drunk or high via early cannabis initiation. There were no other effects of PCE on adult risky sexual behavior or on risk for STIs, after controlling for sex assigned at birth, race, age at sexual initiation, and family history of drug and alcohol problems.ConclusionsAlthough PCE has been associated with earlier initiation of sex in prior studies, PCE was not directly associated with risky adult sex or history of STI. Exposed individuals were at greater risk of sex under the influence of alcohol or drugs via earlier initiation of cannabis use during adolescence.