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.

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.

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.

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.

OBJECTIVE: To evaluate differences in short-term perinatal outcomes between the two prominent screening strategies for gestational diabetes mellitus, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) and Carpenter-Coustan. METHODS: In this single-site, blinded, randomized, comparative effectiveness trial, participants received a nonfasting 50-g oral glucose tolerance test and, if less than 200 mg/dL (less than 11.1 mmol/L), were randomized to further screening with either IADPSG or Carpenter-Coustan criteria. Gestational diabetes treatment occurred per routine clinical care. The primary outcome was incidence of large-for-gestational-age (LGA) neonates. Prespecified secondary outcomes included small-for-gestational-age (SGA) neonates, cesarean birth, and neonatal and maternal composites of adverse perinatal outcomes. Assuming a 15% incidence of LGA neonates in the Carpenter-Coustan group, 782 participants provided more than 80% power to detect a 7% absolute risk reduction with the use of IADPSG; planned recruitment was 920 for anticipated attrition. RESULTS: From June 2015 to February 2019, 1,016 participants were enrolled and 921 were randomized to IADPSG (n=461) or Carpenter-Coustan (n=460) groups. Gestational diabetes incidence (14.4% vs 4.5%, P<.001) and diabetes medication use (9.3% vs 2.4%; P<.001) were more common in the IADPSG group; there were no differences in LGA neonates, either overall (risk reduction 0.90, 97.5% CI 0.53-1.52) or among women without gestational diabetes (risk reduction 0.85, 97.5% CI 0.49-1.48). Those screened with IADPSG had higher rates of neonatal morbidity but fewer study-related adverse events. Rates of SGA neonates, cesarean birth, and maternal morbidity composite did not differ significantly between study groups. CONCLUSIONS: The IADPSG screening criteria resulted in more women diagnosed and treated for gestational diabetes than Carpenter-Coustan without reducing the incidence of LGA birth weight or maternal or neonatal morbidity.

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.

Background Cognitive and behavioral sequelae of prenatal alcohol exposure (PAE) continue to be prevalent in the United States and worldwide. Because these sequelae are also common in other neurodevelopmental disorders, researchers have attempted to identify a distinct neurobehavioral profile to facilitate the differential diagnosis of fetal alcohol spectrum disorders (FASD). We used an innovative, individual participant meta-analytic technique to combine data from six large U.S. longitudinal cohorts to provide a more comprehensive and reliable characterization of the neurobehavioral deficits seen in FASD than can be obtained from smaller samples. Methods Meta-analyses were performed on data from 2236 participants to examine effects of PAE (measured as oz absolute alcohol/day (AA/day)) on IQ, four domains of cognition function (learning and memory, executive function, reading achievement, and math achievement), sustained attention, and behavior problems, after adjusting for potential confounders using propensity scores. Results The effect sizes for IQ and the four domains of cognitive function were strikingly similar to one another and did not differ at school age, adolescence, or young adulthood. Effect sizes were smaller in the more middle-class Seattle cohort and larger in the three cohorts that obtained more detailed and comprehensive assessments of AA/day. PAE effect sizes were somewhat weaker for parent- and teacher-reported behavior problems and not significant for sustained attention. In a meta-analysis of five aspects of executive function, the strongest effect was on set-shifting. Conclusions The similarity in the effect sizes for the four domains of cognitive function suggests that PAE affects an underlying component or components of cognition involving learning and memory and executive function that are reflected in IQ and academic achievement scores. The weaker effects in the more middle-class cohort may reflect a more cognitively stimulating environment, a different maternal drinking pattern (lower alcohol dose/occasion), and/or better maternal prenatal nutrition. These findings identify two domains of cognition-learning/memory and set-shifting-that are particularly affected by PAE, and one, sustained attention, which is apparently spared.

While it is well known that high levels of prenatal alcohol exposure (PAE) result in significant cognitive deficits in children, the exact nature of the dose response is less well understood. In particular, there is a pressing need to identify the levels of PAE associated with an increased risk of clinically significant adverse effects. To address this issue, data have been combined from six longitudinal birth cohort studies in the United States that assessed the effects of PAE on cognitive outcomes measured from early school age through adolescence. Structural equation models (SEMs) are commonly used to capture the association among multiple observed outcomes in order to characterise the underlying variable of interest (in this case, cognition) and then relate it to PAE. However, it was not possible to apply classic SEM software in our context because different outcomes were measured in the six studies. In this paper we show how a Bayesian approach can be used to fit a multi-group multi-level structural model that maps cognition to a broad range of observed variables measured at multiple ages. These variables map to several different cognitive subdomains and are examined in relation to PAE after adjusting for confounding using propensity scores. The model also tests the possibility of a change point in the dose-response function.

OBJECTIVE:With the increasingly permissive legal and social environments regarding marijuana, it is important to understand prenatal marijuana use from the perspective of women who use marijuana. Our objective was to qualitatively describe the marijuana use experiences, beliefs, and attitudes of women who used marijuana during pregnancy. METHODS:We conducted semi-structured interviews with pregnant women who had either reported current marijuana use or had urine testing positive for marijuana. Interviews were transcribed verbatim and analyzed for patterns and themes. RESULTS:Twenty-five pregnant women who used marijuana during their pregnancies participated in our study interviews. Main themes that emerged from the interviews were that women: 1) reported higher amounts of marijuana use prior to pregnancy and attempted to reduce their use once they realized they were pregnant; 2) used marijuana to help with nausea and appetite changes during pregnancy or to improve mood; 3) described marijuana as "natural" and "safe" compared to other substances such as alcohol, tobacco, other recreational drugs, and prescribed medications; 4) had conflicting opinions regarding whether marijuana was addictive; and 5) were uncertain but had some concerns regarding potential risks of prenatal marijuana use. CONCLUSION:Pregnant women who used marijuana in pregnancy held contradictory beliefs about continued use; they reported trying to reduce usage and were worried about potential risks, but also felt that marijuana is more natural and safer than other substances, including prescribed medicines. These findings have implications for how practitioners address prenatal marijuana use and highlight the need for further research on developmental outcomes.

Objectives This study is to examine the association between different diagnostic criteria for gestational diabetes mellitus (GDM) and adverse birth outcomes. Study Design A retrospective cohort study of 5,937 women with a singleton pregnancy was conducted, who completed GDM screening between 24 to 32 weeks gestational age. Four nonoverlapping groups of women defined as: 1) Normal: glucose challenge test (GCT) <130 mg/dL, 2) elevated GCT + normal oral glucose tolerance test (OGTT): abnormal 1 hour GCT + normal 3 hour OGTT, 3) GDM/International Association of Diabetes in Pregnancy Study Group (IADPSG): abnormal 3 hour OGTT by the IADPSG criteria, and 4) GDM/Carpenter-Coustan (CC): diagnosis per CC criteria. We used logistic regression to examine the association between GDM group classification and main outcome of macrosomia and secondary birth outcomes. Results Prevalences were GDM/CC 4.6%, GDM/IADPSG 3.0, and 7.6% overall. GDM/IADPSG group was associated with increased macrosomia (adj OR [odd ratio] 1.87; 95% CI [confidence interval]: 1.08–3.25; p = 0.02), while GDM/CC group was associated with increased preterm birth (adj OR 1.75; 95% CI: 1.05–2.80; p = 0.03). Conclusion Little difference in birth outcomes was found between the two criteria, GDM/CC and GDM/IADPSG. Randomized controlled trials are needed to clarify the risks and benefits of these screening paradigms before their incorporation into clinical practice.

BACKGROUND: Retrospective neuroimaging studies have suggested an association between early cannabis onset and later neurocognitive impairment. However, these studies have been limited in their ability to distinguish substance use risk factors from cannabis-induced effects on neurocognition. We used a prospective cohort design to test whether neurocognitive differences preceded cannabis onset (substance use risk model) and if early cannabis use was associated with poorer neurocognitive development (cannabis exposure model). METHODS: Participants (N = 85) completed a visuospatial working memory task during functional magnetic resonance imaging and multiple cognitive assessments (Wechsler Intelligence Scale for Children-IV, Cambridge Neuropsychological Test Automated Battery) at 12 years of age, before any reported cannabis use (baseline), and at 15 years of age (follow-up: N = 85 cognitive assessments, n = 67 neuroimaging). By follow-up, 22 participants reported using cannabis and/or failed a Delta(9) -tetrahydrocannabinol urine screen (users). RESULTS: At baseline, group differences supported a risk model. Those who would initiate cannabis use by 15 years of age had activation differences in frontoparietal (increased) and visual association (decreased) regions and poorer executive planning scores (Stockings of Cambridge) compared with noninitiators. Limited support was found for a cannabis exposure model. At follow-up, activation in the cuneus displayed a significant cannabis dose-response relationship, although neither cannabis dose nor cuneus activation was associated with cognitive performance. CONCLUSIONS: The purported neurocognitive effects of early cannabis onset may not be due to cannabis initiation alone but also driven by limitations or late development of neurocognitive systems predictive of substance use. In addition, more prolonged cannabis exposure may be required to observe the cognitive effects of early cannabis onset.

Studies have shown that prenatal alcohol exposure (PAE) is related to drinking problems during adulthood, but the level of prenatal exposure associated with young adults' quantity and frequency of alcohol use and drinking problems has not yet been established. The relation between PAE and offspring levels of alcohol use and alcohol abuse/dependency was examined in 608 22-year-olds. Mothers were recruited in early pregnancy and maternal alcohol use data were collected for each trimester of pregnancy. The offspring were assessed at multiple phases from birth to young adulthood. The average daily volume of drinking was calculated based on a self-report questionnaire developed by the Maternal Health Practices and Child Development Project and alcohol abuse/dependence was assessed using the Diagnostic Interview Schedule-IV. Exposure to one or more drinks/day during the first trimester of pregnancy was significantly related to increased levels of drinking at 22 years of age, controlling for other predictors of alcohol use. PAE was also related to two or more symptoms of Alcohol Use Disorder, but not to a full diagnosis of young adult alcohol abuse/dependence. These results indicate that individuals exposed to as little as one drink per day during gestation are at risk of higher levels of drinking and more problems with alcohol by age 22.

Introduction: Prenatal exposures to tobacco and cannabis are associated with combustible cigarette use. This study evaluated pathways from these prenatal exposures to adult electronic cigarette use. We tested whether there were indirect effects of these prenatal exposures via childhood behavior dysregulation, early tobacco use, and adolescent tobacco dependence. Methods: Telephone interviews were conducted with 427 adult offspring (22-33 years old) from 3 prenatal cohorts with trimester-specific data on exposures to tobacco, alcohol, and cannabis. The offspring were 59% Black and 41% White (61% female). Prenatal exposures included quantity/frequency of tobacco, alcohol, and cannabis use by mothers during the first trimester. Using logistic regression and structural equation modeling, we examined the effects of gestational exposures on adult electronic cigarette use via early cigarette use (prior to age 14), controlling for covariates of combustible and electronic cigarette use. Results: There were no effects of childhood behavioral dysregulation on electronic cigarette use. However, there was a significant indirect effect of prenatal exposures to tobacco and cannabis on electronic cigarette use via early adolescent combustible cigarette use and adolescent risk for tobacco dependence. Conclusions: One implication of these findings is that the inter-generational risk for tobacco use conferred via gestational exposures to tobacco and cannabis generalizes to novel products such as electronic cigarettes. These results have implications for public health, as more women use cannabis and co-use cigarettes and cannabis during pregnancy.

Co-use of cannabis and tobacco is increasingly common among women and is associated with tobacco and cannabis dependence and poorer cessation outcomes. However, no study has examined maternal patterns of co-use over time, or the impact of maternal co-use on co-use and drug problems in adult offspring. Pregnant women (M age = 23, range = 18-42; 52% African American, 48% White) were asked about substance use during each trimester of pregnancy, and at 8 and 18 months, 3, 6, 10, 14, 16, and 22 years postpartum. We examined patterns of any maternal cigarette and cannabis use during pregnancy and the postpartum years. As young adults (M age = 22.8 years, range = 21-26), 603 offspring completed the Diagnostic Interview Schedule (DIS). Growth mixture modeling (GMM) was used to identify four maternal trajectories through 16 years postpartum: (1) no co-use (66%), (2) decreasing co-use (16%), (3) postpartum-only co-use (11%), and (4) chronic co-use (7%). Offspring whose mothers were in the decreasing co-use group (co-users primarily during prenatal and preschool periods) were more likely to be co-users than the offspring of non-co-users. Offspring whose mothers were chronic co-users of cigarettes and cannabis were more than twice as likely to have a drug use disorder than young adults whose mothers were not co-users. The results of this study highlight the heterogeneity in maternal co-use of tobacco and cannabis over time, with some women quitting during pregnancy but resuming co-use in the postpartum, and other women co-using during pregnancy but desisting co-use over time. Maternal trajectories of co-use were associated with inter-generational transfer of risk for substance use and dependence in adult offspring.