Dose-response effect of prenatal alcohol exposure on perinatal outcomes.

BACKGROUND: A better understanding of the effects of lower levels of prenatal alcohol exposure (PAE), as a common exposure, is needed. The goal of this study was to examine the effects of mild-moderate PAE and episodic binge drinking on perinatal outcomes. METHODS: The data were obtained from three prospective cohorts with a combined sample of 281 participants: 125 with PAE and 156 without PAE. Alcohol-related measures included the Alcohol Use Disorders Identification Test, timeline follow-back questionnaires (covering the periconceptional period, mid-gestation, and late gestation), and biomarkers. Absolute alcohol per day (AAD) and per drinking day (AADD), number of binge episodes, and maximum number of drinks in a 24-h period were estimated. Perinatal outcomes included gestational age and anthropometric measures. Data were analyzed using correlation and multivariable regression analysis. RESULTS: Among women with PAE, average alcohol consumption across the periconceptional period and pregnancy was 0.37 oz ± 0.74 AA/day (~5 drinks/week). After adjusting for tobacco co-exposure and sociodemographic characteristics, significant associations between all alcohol measures and gestational age at delivery were observed, including cumulative measures of AAD (ß = -0.58; 95% CI: -0.98; -0.17) and AADD (ß = -0.58; 95% CI: -0.90; -0.26) during pregnancy and the periconceptional period. A significant association between the maximum number of drinks in a 24-h period and birth length percentile (ß = -0.70; 95% CI: -1.36; -0.04) was observed in the final model. PAE was associated with lower birth weight percentile in univariate analyses only. CONCLUSIONS: Results of this study demonstrate a negative association between mild-moderate PAE and episodic binge drinking with gestational age at delivery and birth length percentile after controlling for other factors. Robust negative effects of PAE, including in the periconceptional period before pregnancy recognition, on duration of gestation highlight the need for primary prevention efforts aimed at PAE in persons of reproductive age.

Potentially modifiable risk and protective factors affecting mental and emotional wellness in pregnancy.

Introduction: Impaired mental and emotional wellness often co-occurs with prenatal substance use, and both affect infant socio-emotional, cognitive, language, motor, and adaptive behavioral outcomes. Guided by the modified biopsychosocial framework, this study examined the role of common substance exposures during pregnancy (i.e., alcohol and cannabis), socio-cultural factors (social support during pregnancy, adverse childhood experiences), and reproductive health factors on maternal mental health (MMH). Methods: Data were obtained from a prospective cohort study-Ethanol, Neurodevelopment, Infant, and Child Health (ENRICH-2), and included 202 pregnant persons. Alcohol and cannabis exposures were assessed through repeated prospective interviews and a comprehensive battery of drug and ethanol biomarkers. MMH outcomes were evaluated during the third trimester through the Perceived Stress Scale, Edinburgh Depression Scale, Generalized Anxiety Disorders-7, and Post-traumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders. Univariate and multivariable linear regression models evaluated significant predictors of MMH. Results: Results of multivariable analysis indicate that both maternal adverse childhood experiences and alcohol exposure, even at low-to-moderate levels, during pregnancy were associated with poorer scores for most MMH measures, while higher level of social support and Spanish as the primary language at home (as a proxy of enculturation) had protective effects (all p's < 0.05). Conclusion: These findings highlight the importance of assessing substance use, including periconceptional alcohol exposure, and mental health in pregnant persons as closely related risk factors which cannot be addressed in isolation. Our findings also emphasize a strong protective effect of socio-cultural factors on maternal mental and emotional wellbeing-a strong precursor to maternal-infant bonding and infant neurodevelopment.

Independent and Combined Effects of Prenatal Alcohol Exposure and Prenatal Stress on Fetal HPA Axis Development.

Prenatal alcohol exposure (PAE) and prenatal stress (PS) are highly prevalent conditions known to affect fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis. The objectives of this study were to assess the effect of light PAE, PS, and PAE-PS interaction on fetal HPA axis activity assessed via placental and umbilical cord blood biomarkers. Participants of the ENRICH-2 cohort were recruited during the second trimester and classified into the PAE and unexposed control groups. PS was assessed by the Perceived Stress Scale. Placental tissue was collected promptly after delivery; gene and protein analysis for 11ß-HSD1, 11ß-HSD2, and pCRH were conducted by qPCR and ELISA, respectively. Umbilical cord blood was analyzed for cortisone and cortisol. Pearson correlation and multivariable linear regression examined the association of PAE and PS with HPA axis biomarkers. Mean alcohol consumption in the PAE group was ~2 drinks/week. Higher PS was observed in the PAE group (p < 0.01). In multivariable modeling, PS was associated with pCRH gene expression (ß = 0.006, p < 0.01), while PAE was associated with 11ß-HSD2 protein expression (ß = 0.56, p < 0.01). A significant alcohol-by-stress interaction was observed with respect to 11ß-HSD2 protein expression (p < 0.01). Results indicate that PAE and PS may independently and in combination affect fetal programming of the HPA axis.

Assessment of substance exposures in nail clipping samples: A systematic review.

BACKGROUND: Studies of prenatal substance exposure often rely on self-report, urine drug screens, and/or analyses of blood or meconium biomarkers. Accuracy of these measures is limited when assessing exposure over many weeks or months of gestation. Nails are increasingly being considered as a matrix from which to assess substance exposure. This systematic review synthesizes data on the validity of detecting alcohol, nicotine, cannabis, and opioid from nail clippings, with an emphasis on prenatal exposure assessment. METHODS: The systematic review was conducted using PRISMA 2020 guidelines. Seven databases were searched with keywords relevant to the four substances of interest. Results were summarized grouping manuscripts by the exposure of interest with focus on accuracy and feasibility. RESULTS: Of 2384 papers initially identified, 35 manuscripts were included in our qualitative synthesis. Only a few studies specifically looked at pregnant individuals or mother-child dyads. Across the four substances, many studies demonstrated a dose-response relationship between exposure and concentration of analytes in nails. Nail assays appear to detect lower level of exposure compared to hair; however, sample insufficiency, especially for multi-substance assays, remains a limitation. CONCLUSIONS: Based on the reviewed studies, nail clippings are an acceptable and potentially preferable matrix for the evaluation of these four prenatal substances when sampling frequency and/or study design necessitates assessment of past exposures over an extended period. Nails have the advantage of infrequent sampling and minimal invasiveness to assess a broad exposure period. Future studies should examine validity of analytes in toenail versus fingernail clippings.

Impact of low-level prenatal alcohol exposure and maternal stress on autonomic regulation.

BACKGROUND: Prenatal alcohol exposure (PAE) impacts the neurodevelopment of the fetus, including the infant's ability to self-regulate. Heart rate variability (HRV), that is, the beat-to-beat variability in heart rate, is a non-invasive measurement that can indicate autonomic nervous system (ANS) function/dysfunction. METHODS: The study consisted of a subset of our ENRICH-2 cohort: 80 participants (32 PAE and 48 Controls) who had completed three visits during pregnancy. The participants completed a comprehensive assessment of PAE and other substances throughout pregnancy and assessments for stress, anxiety, and depression in the third trimester. At 24 h of age, infant HRV was assessed in the hospital during the clinically indicated heel lance; 3- to 5-min HRV epochs were obtained during baseline, heel lancing, and recovery episodes. RESULTS: Parameters of HRV differed in infants with PAE compared to Controls during the recovery phase of the heel lance (respiratory sinus arrhythmia (RSA) and high-frequency (HF), p < 0.05). Increased maternal stress was also strongly associated with abnormalities in RSA, HF, and low-frequency / high-frequency (LF/HF, p's < 0.05). CONCLUSIONS: Alterations in ANS regulation associated with PAE and maternal stress may reflect abnormal development of the hypothalamic-pituitary-adrenal axis and have long term implications for infant responsiveness and self-regulation. IMPACT: Previous studies have focused on effects of moderate to heavy prenatal alcohol exposure (PAE) on autonomic dysregulation, but little is known about the effects of lower levels of PAE on infant self-regulation and heart rate variability (HRV). Prenatal stress is another risk factor for autonomic dysregulation. Mild PAE impacts infant self-regulation, which can be assessed using HRV. However, the effect of prenatal stress is stronger than that of mild PAE or other mental health variables on autonomic dysregulation.

The effect of the COVID-19 pandemic on substance use patterns and physiological dysregulation in pregnant and postpartum women.

BACKGROUND: The SARS-CoV-2/COVID-19 pandemic has been associated with increased stress levels and higher alcohol use, including in pregnant and postpartum women. In the general population, alcohol use is associated with dysregulation in the autonomic nervous system (ANS), which is indexed by heart rate variability (HRV). The objectives of this study were to: (1) characterize changes in substance use during the SARS-CoV-2/COVID-19 pandemic via a baseline self-report survey followed by mobile ecological momentary assessment (mEMA) of substance use; and (2) examine the associations between momentary substance use and ambulatory HRV measures in pregnant and postpartum women. METHODS: Pregnant and postpartum women were identified from the ENRICH-2 prospective cohort study. Participants were administered a baseline structured phone interview that included the Coronavirus Perinatal Experiences (COPE) survey and ascertained the prevalence of substance use. Over a 14-day period, momentary substance use was assessed three times daily, and HRV measurements were captured via wearable electronics. Associations between momentary substance use and HRV measures (root mean square of successive differences [RMSSD] and low frequency/high frequency [LF/HF] ratio) were examined using a mixed effects model that included within-subject (WS) and between-subject (BS) effects and adjusted for pregnancy status and participant age. RESULTS: The sample included 49 pregnant and 22 postpartum women. From a combination of a baseline and 14-day mEMA surveys, 21.2% reported alcohol use, 16.9% reported marijuana use, and 8.5% reported nicotine use. WS effects for momentary alcohol use were associated with the RMSSD (ß = -0.14; p = 0.005) and LF/HF ratio (ß = 0.14; p = 0.01) when controlling for pregnancy status and maternal age. No significant associations were observed between HRV measures and instances of marijuana or nicotine use. CONCLUSIONS: These findings highlight the negative effect of the SARS-CoV-2/COVID-19 pandemic on the psychological health of pregnant and postpartum women associated with substance use, and in turn, ANS dysregulation, which potentially puts some women at risk of developing a substance use disorder.

Impulsivity and Alcohol Use during Pregnancy and Postpartum: Insights from Novel Methodological Approaches within the Context of the COVID-19 Pandemic.

Impaired emotion regulation and impulsivity have been linked to substance use. This study evaluated the association between emotion regulation difficulties-specifically impulsivity-and substance use within the context of the COVID-19 pandemic among pregnant (n = 49) and postpartum (n = 20) women. Participants from a prospective cohort ENRICH-2 completed a baseline phone survey of COVID-19-related experiences and impulsivity followed by a 14-day (3x/day) mobile ecological momentary assessment (mEMA) of impulsivity and substance use. Between-subject (BS) and within-subject (WS) associations for baseline impulsivity and momentary impulsivity with respect to substance use were examined using mixed effects models. At the BS level, momentary impulsivity scores that were higher than the overall group average were positively associated with subsequent momentary reports of marijuana use (ß = 1.25; p = 0.04) when controlling for pregnancy status and COVID-19-related stress. At the WS level, momentary impulsivity scores that were higher than an individual's average score were positively associated with subsequent reports of momentary alcohol use (ß = 0.08; p = 0.04). This research supports the idea that impulsivity varies based on individual situations, such as stress associated with the COVID-19 pandemic, and may be an important correlate of substance use in pregnant and postpartum women. Future research might consider investigation of additional factors, which may serve to moderate or mediate the relationship between impulsivity and substance use.

Effects of medications for opioid use disorder (MOUD) on fetal brain and cranial measurements.

BACKGROUND: The use and misuse of opioids, as well as opioid use disorder (OUD) have increased remarkably among reproductive-aged and pregnant women. As many as 25% of pregnant women who report non-medical opioid use in the past month also report concurrent alcohol use. While teratogenic effects of alcohol are well established, there are limited studies evaluating fetal intracranial effects associated with medications for OUD (MOUD) and concurrent use of MOUD and alcohol during pregnancy. The objective of this study was to determine the effect of MOUD, with and without concomitant alcohol use, on fetal intracranial measurements. The type of maternal MOUD therapy (methadone vs. buprenorphine) was also examined. METHODS: This study was a secondary analysis of a prospective cohort study among participants (n = 196) assigned into three groups (MOUD [n = 94], MOUD+Alcohol [n = 47], and unexposed controls [n = 55]). Co-exposure with either methamphetamines or cocaine were exclusionary criteria; other co-exposures were carefully characterized with prospective repeated self-report measures and biomarkers. Fetal ultrasound measurements at 18-22 weeks (2nd trimester) and 28-32 weeks (early 3rd trimester) were compared among study groups. In addition to standard morphometrics, we performed specialized intracranial measurements of caval-calvarial distance (CCD), frontal lobe width (FLW), frontal lobe length (FLL), and fronto-thalamic distance (FTD). RESULTS: Brain and cranial measurements between MOUD, with or without alcohol co-exposure, and unexposed controls were generally not significantly different in multivariable analyses. Subjects in the MOUD groups had earlier gestational age at delivery and lower birth weight and birth weight percentile compared to unexposed controls with differences driven primarily by the methadone subgroup. Significant differences in standard and specialized intracranial indices at both second and third trimester as well as differences in the change of HC percentile over time were observed in the methadone subgroup compared to controls, while no differences between buprenorphine subgroup and controls were observed for any measures. CONCLUSION: Patients receiving methadone therapy might require closer monitoring during pregnancy; however, detailed imaging of the fetal brain other than the standard measurements might not be warranted.

A Qualitative Scoping Review of Early-Terminated Clinical Trials Sponsored by the Department of Veterans Affairs Cooperative Studies Program From 2010 to 2020.

Increasing attention has been paid to the risks and benefits of terminating large clinical trials before reaching prespecified targets, because such decisions can greatly affect the implementation of findings. The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) is a research infrastructure dedicated to conducting high-quality clinical research. A scoping review was performed to characterize barriers preventing the attainment of prespecified recruitment, statistical power, or sample-size targets in VA CSP trials. A trial was eligible for inclusion if the trial was sponsored by the VA CSP, primary findings were published within the last 10 years, and a decision was made to terminate enrollment or follow-up before meeting a priori recruitment or endpoint targets. In 11 of 29 included trials (37.9%), a decision was made to terminate the trial early. The most common reason for early termination was related to under-recruitment (n = 5). Other reasons included early detection of safety signals (n = 2), futility (n = 1), and benefit (n = 1). This review highlights recruitment as a critical facet of trial conduct that may hinder the production of high-quality data and thus warrant additional attention. Solutions to enhance recruitment now implemented by the VA CSP, including dedicated enrollment infrastructure and screening facilitated by informatics approaches, show promise in reducing this cause for early termination.

Early developmental trajectory of children with prenatal alcohol and opioid exposure.

BACKGROUND: With significant increases in opioid use/misuse and persistent high prevalence of prenatal alcohol exposure (PAE), identifying infants at risk for long-term developmental sequelae due to these exposures remains an urgent need. This study reports on developmental outcomes in young children from a prospective cohort, ENRICH-1, which recruited pregnant women and followed up maternal-infant pairs. METHODS: Subjects were assigned to four study groups based on prenatal use of medications for opioid use disorder (MOUD), PAE, MOUD+PAE, and unexposed controls (UC). Mixed effects modeling was used to evaluate changes in the Bayley Scales of Infant Development-III (BSID-III) Cognitive, Language, and Motor scores between 6 and 20 months. RESULTS: There was a significant three-way interaction (MOUD-by-PAE-by-Time) with respect to the BSID-III Cognitive (p = 0.045) and Motor (p = 0.033) scales. Significant changes between the two evaluations were observed for MOUD group in Cognitive and Language scores; for PAE group in Cognitive, Language, and Motor scores, and for MOUD+PAE group in Language scores after adjusting for child sex and family socio-economic status. The developmental scores for the UC remained stable. CONCLUSION: Observed decline in neurodevelopmental scores during the first 2 years of life emphasizes the importance of a longitudinal approach when evaluating children with prenatal polysubstance exposure. IMPACT: BSID-III scores were stable during the first 2 years of life for unexposed children. BSID-III scores declined for children with prenatal exposures to alcohol and/or opioids. Standard developmental tests may not be sensitive enough during the first year of life. Findings emphasize the need for repeated evaluations of children who are at high risk.

Decreased resting-state alpha peak frequency in children and adolescents with fetal alcohol spectrum disorders or prenatal alcohol exposure.

Prenatal alcohol exposure (PAE) can result in long-lasting changes to physical, behavioral, and cognitive functioning in children. PAE might result in decreased white matter integrity, corticothalamic tract integrity, and alpha cortical oscillations. Previous investigations of alpha oscillations in PAE/fetal alcohol spectrum disorder (FASD) have focused on average spectral power at specific ages; therefore, little is known about alpha peak frequency (APF) or its developmental trajectory making this research novel. Using resting-state MEG data, APF was determined from parietal/occipital regions in participants with PAE/FASD or typically developing controls (TDC). In total, MEG data from 157 infants, children, and adolescents ranging in age from 6 months to 17 years were used, including 17 individuals with PAE, 61 individuals with an FASD and 84 TDC. In line with our hypothesis, we found that individuals with PAE/FASD had significantly reduced APF relative to TDC. Both age and group were significantly related to APF with differences between TDC and PAE/FASD persisting throughout development. We did not find evidence that sex or socioeconomic status had additional impact on APF. Reduced APF in individuals with an FASD/PAE may represent a long-term deficit and demonstrates the detrimental impact prenatal alcohol exposure can have on neurophysiological processes.

The maternal-placental-fetal interface: Adaptations of the HPA axis and immune mediators following maternal stress and prenatal alcohol exposure.

This review addresses underlying physiological, cellular, and molecular factors that alter the developing fetal brain stress circuits and responses of the hypothalamic-pituitary-adrenal (HPA) axis caused by maternal stress and prenatal alcohol exposure (PAE). An emphasis is placed on the contribution of the placenta following maternal stress separately, and as a co-occurrence with PAE. Altered fetal HPA axis ultimately results in dysregulation of the brain stress-response system long after birth and possibly lifelong. Additional consideration of the role of placentally-derived endocrine and sex hormones, as well as a brief discussion of epigenetic mechanisms of altered placental expression of genes encoding the glucocorticoid receptor and the enzymes 11ß-HSD that rapidly convert glucocorticoids into its active or inactive forms are reviewed. Data highlighting the strong, reciprocal interactions between the neuroimmune and neuroendocrine systems during fetal development that are impacted by maternal stress and PAE are considered, emphasizing the role of the placenta as a key contributor to the dysregulation of these systems. In view of the maternal-placental-fetal interface, important physiological, cellular, and molecular factors underlying later life dysregulated stress responses are additionally considered. Literature from animal models of PAE and maternal stress is reviewed that support clinical observations of the effect of maternal stress and alcohol exposure during fetal development on later-life adult stress responses and associated mood dysregulation. An appreciation of dysregulated stress responses in individuals with fetal alcohol spectrum disorders (FASD) are addressed given the greater prevalence of adult dysregulated stress responses and a greater co-occurrence of mood disorders in individuals diagnosed with FASD.

Prenatal opioid-exposed infant extracellular miRNA signature obtained at birth predicts severity of neonatal opioid withdrawal syndrome.

Prenatal opioid exposure (POE) is commonly associated with neonatal opioid withdrawal syndrome (NOWS), which is characterized by a broad variability in symptoms and severity. Currently there are no diagnostic tools to reliably predict which infants will develop severe NOWS, while risk stratification would allow for proactive decisions about appropriate clinical monitoring and interventions. The aim of this prospective cohort study was to assess if extracellular microRNAs (miRNAs) in umbilical cord plasma of infants with POE could predict NOWS severity. Participants (n = 58) consisted of pregnant women receiving medications for opioid use disorder and their infants. NOWS severity was operationalized as the need for pharmacologic treatment and prolonged hospitalization (≥ 14 days). Cord blood miRNAs were assessed using semi-quantitative qRT-PCR arrays. Receiver operating characteristic curves and area under the curve (AUC) were estimated. The expression of three miRNAs (miR-128-3p, miR-30c-5p, miR-421) predicted need for pharmacologic treatment (AUC: 0.85) and prolonged hospitalization (AUC: 0.90). Predictive validity improved after two miRNAs (let-7d-5p, miR-584-5p) were added to the need for pharmacologic treatment model (AUC: 0.94) and another two miRNAs (let-7b-5p, miR-10-5p) to the prolonged hospitalization model (AUC: 0.99). Infant cord blood extracellular miRNAs can proactively identify opioid-exposed neonates at high-risk for developing severe NOWS.

Effects of prenatal opioid and alcohol exposures on immune and serotonin factors in human placenta.

PURPOSE: Opioids and alcohol impact critical serotonin (5-HT) function in the developing placenta and fetus through the actions of immune proinflammatory factors. Yet, possible convergent effects of opioids and alcohol on human placental toll-like receptor 4 (TLR4) activation and subsequent 5-HT homeostasis remain entirely unknown. The purpose of this study was to examine the effect of prenatal exposure to opioids with or without prenatal alcohol exposure (PAE) on the expression of key placental immune and serotonin signaling factors in human placental tissue obtained from a well-characterized prospective cohort. METHODS: Data were collected from a subset of participants enrolled in the prospective pre-birth Ethanol, Neurodevelopment, Infant, and Child Health (ENRICH-1) cohort. Women were recruited and classified into four study groups: 1) PAE (n = 20); 2) those taking medications for opioid use disorder (MOUD; n = 28), 3) concurrent PAE and MOUD (n = 20); and 4) controls (HC; n = 20) based on prospective, repeated self-report, and biomarker analysis. Placenta samples underwent tissue processing to identify mRNA for TLR4, nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), serotonin transporter (SERT), tryptophan hydroxylase (TPH1), indoleamine 2,3-Dioxygenase 1 (IDO) as well as protein concentrations of TLR4, IL-1ß, TNF-α, SERT. To consider the association between study group and mRNA/protein expression of our targets, multivariable regression models were developed with inclusion of a priori selected covariates. RESULTS: There was a significant negative association between PAE and SERT mRNA (ß = -0.01; p < 0.01) and a positive association with TPH1 mRNA expression (ß = 0.78; p < 0.05). In addition, there was a negative association between MOUD and TNF-α protein expression (ß = -0.12; p < 0.05). CONCLUSIONS: This study provides the first evidence that PAE may inhibit SERT expression while simultaneously promoting increased TPH1 protein expression in human placenta. This may result in increased 5-HT in fetal circulation known to affect neurodevelopment. Our data suggest that opioids and alcohol may disturb the bidirectional, dynamic interaction between the placental immune and serotonin system. Given the implication for brain development and health across the life-span further investigation of these critical mechanisms in well-defined cohorts is required.

Prevalence of marijuana use in pregnant women with concurrent opioid use disorder or alcohol use in pregnancy.

BACKGROUND: A quarter of pregnant women use alcohol, 6.5/1000 deliveries are affected by opioid use disorder (OUD), and the prevalence of cannabis use in pregnant women is increasing. However, marijuana co-exposure in polysubstance-using women is not well described. METHODS: The well-characterized ENRICH-1 cohort (n = 251), which focused on the effects of two primary exposures of interest-opioids and alcohol, was used to (1) estimate the prevalence/frequency of marijuana use in those with OUD and/or alcohol use, and (2) examined correlates of marijuana use. Participants were classified into an OUD group (n = 125), Alcohol group (n = 69), and concurrent OUD and Alcohol (OUD + Alcohol) group (n = 57). Self-report and biomarkers ascertained substance use. Multivariable logistic regression identified correlates of marijuana use. RESULTS: The prevalence of any marijuana use in pregnancy was 43.2%, 52.6%, and 46.4% in the OUD, OUD + Alcohol, and Alcohol groups, respectively. Correspondingly, weekly or daily use was reported by 19.4%, 21.0%, and 24.6% of participants. In the OUD and OUD + Alcohol groups, the proportion of women using marijuana was significantly higher in those taking buprenorphine (45.8% and 58.3%, respectively) compared to women using methadone (37.5% and 42.9%, respectively). Mean maternal age was lower in women who used marijuana in all three groups compared to non-marijuana users. Independent correlates of marijuana use (controlling for group, race/ethnicity, education, and smoking) were maternal age (adjusted Odds Ratio (aOR) per 5-year increment 0.61; (95% CI 0.47, 0.79)), and polysubstance use (aOR 2.02; 95% CI 1.11, 3.67). There was a significant interaction between partnership status and group: among women who were not in a partnership, those in the OUD and OUD + Alcohol groups had lower odds of marijuana use relative to the Alcohol group. For women in the Alcohol group, partnered women had lower odds of marijuana use than un-partnered women (aOR 0.12; 95% CI: 0.02, 0.68). CONCLUSIONS: Results indicate a relatively high prevalence and frequency of marijuana use in pregnant women being treated for OUD and/or women consuming alcohol while pregnant. These results highlight the need for ongoing risk reduction strategies addressing marijuana use for pregnant women receiving OUD treatment and those with alcohol exposure.

CONSIDER New Mexico: Effects of naloxone training among pharmacists and pharmacy technicians.

BACKGROUND: Pharmacists serve a critical role in providing health care, especially in medically underserved areas. Despite the opioid crisis and legislation in most states allowing pharmacists to dispense naloxone without a prescription from another provider, pharmacists face multiple barriers to dispensing naloxone. OBJECTIVE: This study tested the effectiveness of CONSIDER New Mexico, an innovative educational initiative designed to increase naloxone dispensing by pharmacies. METHODS: A quasi-experimental study was conducted in New Mexico in 2019-2020. Community pharmacists and pharmacy technicians were recruited from a purposive sample of pharmacies. Data were collected through pre- and postintervention surveys with 65 pharmacists and 44 technicians from 49 pharmacies. Data analysis included hybrid fixed-effects regression models of variables associated with pre-post intervention change in intent to dispense naloxone and generalized least squares with maximum likelihood estimation for pre-post intervention change in naloxone dispensing. RESULTS: Positive intervention effects were observed for measures of normative beliefs, self-efficacy, and intent to dispense naloxone (P < 0.05). Changes in normative beliefs and self-efficacy were associated with greater intent to offer naloxone to patients (P < 0.05). In addition, the median number of naloxone prescriptions dispensed per month increased 3.5 times after intervention. A statistically significant positive association was observed between the intervention and naloxone dispensing after adjusting for other factors (P < 0.001). Pharmacies providing more than 4 additional health services were more likely to increase naloxone dispensing postintervention than pharmacies offering not more than 2 services (P < 0.01). This difference averaged 19 naloxone prescriptions per month. Estimated change in dispensing postintervention was statistically significantly lower at independent, clinic-based, and other pharmacies where an average of 36 fewer naloxone prescriptions were dispensed per month compared with chain drug stores (P = 0.03). CONCLUSION: The CONSIDER New Mexico intervention effectively increased self-efficacy, intent to dispense, and naloxone dispensing. Findings will inform future research examining widespread dissemination and implementation of the intervention and the sustainability of intervention effects.

Severity of neonatal opioid withdrawal syndrome with prenatal exposure to serotonin reuptake inhibitors.

OBJECTIVE: To evaluate the severity of neonatal opioid withdrawal syndrome (NOWS) in infants prenatally exposed to medications for opioid use disorder (MOUD) and serotonin reuptake inhibitors (SRI). METHODS: A prospective cohort included 148 maternal-infant pairs categorized into MOUD (n = 127) and MOUD + SRI (n = 27) groups. NOWS severity was operationalized as the infant's need for pharmacologic treatment with opioids, duration of hospitalization, and duration of treatment. The association between prenatal SRI exposure and the need for pharmacologic treatment (logistic regression), time-to-discharge, and time-to-treatment discontinuation (Cox proportional hazards modeling) was examined after adjusting for the type of maternal MOUD, use of hydroxyzine, other opioids, benzodiazepines/sedatives, alcohol, tobacco, marijuana, gestational age, and breastfeeding. RESULTS: Infants in the MOUD + SRI group were more likely to receive pharmacologic treatment for NOWS (OR = 3.58; 95% CI: 1.31; 9.76) and had a longer hospitalization (median: 11 vs. 6 days; HR = 0.54; 95% CI: 0.33; 0.89) compared to the MOUD group. With respect to time-to-treatment discontinuation, no association was observed in infants who received treatment (HR = 0.59; 95% CI: 0.26, 1.32); however, significant differences were observed in the entire sample (HR = 0.55; 95% CI: 0.34, 0.89). CONCLUSIONS: Use of SRIs among pregnant women on MOUD might be associated with more severe NOWS. IMPACT: A potential drug-drug interaction between maternal SRIs and opioid medications that inhibit the reuptake of serotonin has been hypothesized but not carefully evaluated in clinical studies. Results of this prospective cohort indicate that the use of SRIs among pregnant women on MOUD is associated with more severe neonatal opioid withdrawal syndrome. This is the first prospective study which carefully examined effect modification between the type of maternal MOUD and SRI use on neonatal outcomes. This report lays the foundation for treatment optimization in pregnant women with co-occurring mental health and substance use disorders.

Maternal verbal scaffolding: association with higher language skills for 20-month-old children with prenatal polysubstance exposure.

BACKGROUND: The number of children with prenatal polysubstance exposure is increasing. Supportive mother-child interaction is a protective factor, which can ameliorate adverse effects of prenatal polysubstance exposure on developmental outcomes. AIM: To examine the role of maternal verbal scaffolding on cognitive and language development in children with prenatal polysubstance exposure. STUDY DESIGN: Pregnant women were recruited, and we prospectively followed mother-child dyads to 20 months of age. This analysis included 66 dyads (33 healthy controls and 33 with prenatal polysubstance exposure). Multivariable linear regression modelling was used to examine the cross-sectional association between maternal scaffolding and Bayley Scales of Infant and Toddler Development (BSID-III) score, as well as an interaction between the study group and scaffolding score. OUTCOME MEASURES: The BSID-III cognitive and language score was used. Videotaped mother-child play was coded to obtain a maternal verbal scaffolding score. Effect sizes were measured using average differences in scores between groups. RESULTS: There was no evidence of an association between study group and maternal scaffolding scores. Children in the polysubstance exposure group had lower cognitive and language scores compared to controls, but this association was not statistically significant after controlling for maternal education. Maternal scaffolding was predictive of language scores, with scores increasing by 1.24 points on average (95% CI: 0.42, 2.06) for every 1-point increase in scaffolding score after adjustment for covariates. There was no evidence of a study group-by-scaffolding interaction with respect to the language or cognitive scores. CONCLUSIONS: Maternal scaffolding during play was associated with language development in children with and without prenatal polysubstance exposure.

A socioecological framework for engaging substance-using pregnant persons in longitudinal research: Multi-stakeholder perspectives.

OBJECTIVE: Understanding the impact of substance use during pregnancy on fetal development and child health is essential for designing effective approaches for reducing prenatal substance exposures and improving child outcomes. Research on the developmental impacts of prenatal substance exposure has been limited by legal, ethical, and practical challenges. This study examined approaches to engage substance-using (with an emphasis on opioids) pregnant persons in longitudinal research, from multi-stakeholder perspectives. METHODS: The present study solicited the expertise of 1) an advisory group of community stakeholders, including people with lived experienced of opioid/substance use; and 2) an online survey with content experts. Qualitative analysis examined facilitators and barriers to recruiting and retaining substance-using pregnant persons through a socioecological lens at the individual, interpersonal, organizational, community, and policy levels. RESULTS: Stakeholders (N = 19) prioritized stigma, loss of confidentiality, legal consequences, and instability (e.g., homelessness and poverty) as important barriers that prevent substance-using persons from enrolling in research studies. Of 70 survey respondents, most self-identified as researchers (n = 37), followed by clinicians (n = 19), and 'others' (n = 14). Survey respondents focused on retention strategies that build trusting relationships with participants, including incentives (e.g., transportation and childcare support), participant-friendly study design, and team-related factors, (e.g., attitudes and practices). CONCLUSION: The stakeholder input and survey data offer key insights strengthening our understanding of facilitators and barriers to research participation, and ways to overcome barriers among substance-using pregnant persons. A socioecological framework can be used to identify and address these factors to increase recruitment and long-term retention of high-risk populations.

Post-discharge healthcare utilization in infants with neonatal opioid withdrawal syndrome.

The opioid epidemic in the United States has led to a significant increase in the incidence of neonatal opioid withdrawal syndrome (NOWS); however, the understanding of long-term consequences of NOWS is limited. The objective of this study was to evaluate post-discharge healthcare utilization in infants with NOWS and examine the association between NOWS severity and healthcare utilization. A retrospective cohort design was used to ascertain healthcare utilization in the first year after birth-related discharge using the CERNER Health Facts® database. ICD-9/ICD-10 diagnostic codes were used to identify live births and to classify infants into two study groups: NOWS and uncomplicated births (a 25% random sample). Evaluated outcomes included rehospitalization, emergency department (ED) visits within 30-days and one-year after discharge, and a composite one-year utilization event (either hospitalization or emergency department visit during that year). NOWS severity was operationalized as pharmacologic treatment, length of hospitalization, and medical conditions often associated with NOWS. In 3,526 infants with NOWS (restricted to gestational age ≥ 33 weeks), NOWS severity was associated with an increase in composite one-year utilization (OR: 1.1; 95% CI: 1.04-1.2) after adjusting for prematurity, sepsis, jaundice, use of antibiotics, infant sex, insurance status, race, hospital bed size, year of birth, and census division. In a subset of full-term infants (3008 with NOWS and 88,452 uncomplicated births), having a NOWS diagnosis was associated with higher odds of a 30-day (OR: 1.6; 95% CI: 1.03-2.4) and one-year rehospitalization (OR: 1.6; 95% CI: 1.1-2.4) after adjusting for infant sex, race, type of medical insurance, hospital location, census division, year of primary encounter, hospital bed size, and medical conditions. This study found higher healthcare utilization during the first year of life in infants diagnosed with NOWS, especially those with severe NOWS. Findings suggest a need for closer post-discharge follow-up and management of infants with NOWS.