Basic Science	Opioid use disorder is a syndrome commonly associated with multiple potentially deleterious exposures other than opiates and several adverse pregnancy outcomes including poor fetal growth, preterm birth, fetal loss, stillbirths and birth defects. ○ It is unlikely that the associated adverse pregnancy outcomes will be scientifically rigorously attributable to individual exposures among the numerous exposures that are characteristic of the syndrome. ○ Many covariates (exposures) that are strongly associated with opiate use include tobacco, alcohol, benzodiazepines, cocaine and other substances of abuse, poor nutrition, anemia, STIs, un-planned and un-desired pregnancies, poor educational attainment, low socio-economic status, poor housing conditions, exposure to and legitimate fear of violence ○ Absent scientifically rigorous data on causation, how should potentially deleterious exposures be prioritized for interventions? ○ Are there undiscovered mechanisms of adverse biologic effects on placental function of potentially deleterious exposures? What are the developmental and inherited genetic variations in opioid action and metabolism?
Prenatal Screening for Opioid Use Disorder	What is the best method for screening? ○ Modality (computer questionnaire, in person interview (with whom), biological sample) ○ Optimal time, interval, and frequency ○ Optimal tool (5Ps, SUR-P, etc.) ○ What are the barriers to screening (real and perceived)? How to maintain confidentiality and trust while minimizing judgmental behavior and punitive implications?
OB/Gyn Prenatal Care	How best to structure comprehensive care to bring all resources to women? What is optimal assessment for fetal well-being?
Medication-Assisted Treatment and Detoxification	What is the best technique to engage women in treatment? ○ Include women recovering from opioid use disorders? ○ Develop a screening tool to predict probability of relapse. ○ Will physiologic measures of opioid withdrawal be more useful than simply assessing cravings? What are the optimal safety, efficacy, and treatment approaches during pregnancy? ○ Methadone vs. buprenorphine ○ Combinations (buprenorphine + naloxone, naloxone, or naltrexone) ○ Impact of other agents (e.g. psychotropic medications, “mood stabilizers”) Can “precision medicine” inform the appropriate dosing for all medications throughout pregnancy? Post-partum? During breastfeeding? ○ Which medication works best for which patients? ○ Need pharmacokinetic/pharmacodynamics studies for all medications during pregnancy and with breastfeeding ○ Need test for mother’s metabolism (fast vs. slow metabolizers) – may need different dosing schedules How long do patients need medication? What is the best way to wean them? Is there a sub-group of women with opioid use disorder who will be successful with detoxification therapy? ○ Can we reliably identify them a priori? ○ Need evidence for optimal fetal assessment and efficacy in this scenario ○ Role of benzodiazepines and adjunct medications (e.g., adrenergic blockade) with respect to success ○ Need medical interventions for known consequences of detoxification ○ Need trials of opioid detoxification with fetal monitoring and excellent follow-up, analyzed by intent to treat ○ Anticipate and minimize potential relapse rates if detox is undertaken Understand the pathophysiology of detoxification during pregnancy: maternal, uteroplacental function, and fetal effects
Pain management intrapartum	Optimal/appropriate agonist dosing ○ Integration of narcotic and non-narcotic medications ○ Effect modifiers (e.g., poly-drug use, smoking, and stress)
Pain management postoperative	Comparative effectiveness of non-opioid alternatives for post-cesarean pain control (e.g., gabapentin, transversus abdominis plane block, IV acetaminophen) Education and changing physician practices in postpartum pain management What is the risk of overdose in those using illicit opioids or on high-dose chronic opioid therapy? ○ Is pregnancy an independent risk factor for overdose? If so, is it mediated by sleep-disordered breathing? Post-cesarean opioid use. How to align the amount of opioid medication prescribed with what is needed? Implications for relapse?
Post-Partum Care and Support	Comparative effectiveness and safety of buprenorphine management strategies after delivery ○ Continuing buprenorphine or replacing it with pure μ-agonists Preventing postpartum relapse ○ What are the risk factors for relapse following delivery? ○ Do opioid type, dosing, and management strategies affect risk of relapse? Breastfeeding ○ Improve prenatal education/counseling of the benefits of breastfeeding ○ What interventions could increase breastfeeding initiation rates and prolong breastfeeding duration? ○ What are the causal pathways between breastfeeding and the decreased occurrence and severity of NAS? Contraception ○ How to improve access, availability, acceptance and affordability of LARC? ○ How to increase regular dual use of condoms and non-barrier methods to prevent STIs? Post-partum Depression ○ What factors correlate with development of postpartum depression? ○ What are the best depression screening tools for women with substance use disorder, including frequency and timing of screening in prenatal and postpartum periods? ○ Who should be treated prophylactically to prevent post-partum depression?
Neonatal Screening and Assessment for Neonatal Abstinence Syndrome	What are the best methods for identification and screening for NAS? ○ Need biomarker for NAS as a physiologic state e.g. epinephrine or cortisol levels for NAS ○ Need lab-on-a-chip method for rapid testing for NAS ○ What are the predictive factors for development of NAS? Diagnostic assays for who will develop NAS and how they will respond to therapies What is the best method for assessing development of infants with NAS? ○ What factors most accurately define the appropriate observation period for infants at risk for NAS? How often should neonates be evaluated? ○ Develop objective tools using technology-assisted assessment ○ Individualized, comprehensive assessment to identify those infants most susceptible to poor developmental outcomes that considers: ▪ Infant state ▪ Genetic and epigenetic information ▪ Pharmacologic management ▪ Neurobehavioral functioning ▪ Soothing techniques to avoid pharmacotherapy when possible ▪ Environment ▪ Adaptable for infant gestational and developmental age ○ Test scoring systems and assessment protocols against each other What factors affect risk profiles for infants? Different substance exposures may lead to the same symptoms; need ability to distinguish them to determine best therapy. ○ Population heterogeneity ○ Dose and gestational age of exposure to maternal opioids
Treatment of Neonatal Abstinence Syndrome	What is the optimal initial drug for treatment of NAS? What are appropriate indications for a second drug? Can genetic or epigenetic analyses be combined with antenatal exposures to tailor an optimal treatment regimen? What is the role of poly-drug use? What criteria best select babies and families for outpatient management? What resources are needed for safe and effective outpatient management?
Neonatal Discharge and Follow-up	What are the longer-term development outcomes for children prenatally exposed to agonist or antagonist medications? ○ Exposure is different based on variations in neonatal metabolism ○ No data on exposure timing and long-term developmental outcomes ○ Role of the environment is critical to outcome ○ Latent effects How does maternal psychiatric co-morbidities and propensity for substance abuse affect child outcomes? What are the barriers to care related to state-regulations? Do state-specific regulations affect screening, treatment, and infant outcomes?