Risk factors for food insecurity and association with prenatal care utilization among women who took opioids during pregnancy.

Background: Food insecurity during pregnancy is associated with poorer outcomes for both mothers and their newborns. Given the ongoing opioid crisis in the United States, mothers who take opioids during pregnancy may be at particular risk of experiencing food insecurity. Methods: This research utilized data from 254 biological mothers of infants in the Advancing Clinical Trials in Neonatal Opioid Withdrawal Syndrome (ACT NOW) Outcomes of Babies with Opioid Exposure (OBOE) Study. We examined factors associated with food insecurity among mothers of infants with antenatal opioid exposure and their unexposed (control) counterparts. Chi-square tests and logistic regression were used to compare food insecurity by sociodemographic characteristics, opioid use, prior traumatic experiences, and housing instability. Similar analyses were conducted to examine the relationship between food insecurity during pregnancy and receipt of adequate prenatal care. Results: Overall, 58 (23%) of the mothers screened positive for food insecurity. Food insecurity was more common among mothers who took opioids during pregnancy (28% vs. 14%; p =0.007), had public insurance (25% vs. 8%; p = 0.027), had housing instability (28% vs. 11%, p = 0.002), experienced three or more adverse experiences in their childhood (37% vs. 17%; p < 0.001), and reported physical or emotional abuse during their pregnancy (44% vs. 17%; p < 0.001). Mothers with food insecurity during pregnancy were less likely to have received adequate prenatal care (78% vs. 90%; p = 0.020). This difference remained after controlling for demographic characteristics (AOR (95% CI) = 0.39 (0.16, 1.00), p = 0.049). Conclusions: This study adds to the body of evidence supporting the need for screening and development of interventions to address food insecurity during pregnancy, particularly among mothers of infants with antenatal opioid exposure, for which limited data are available. The findings revealed that food insecurity frequently co-occurs with housing instability and prior trauma, indicating that a multifaceted intervention incorporating principles of trauma-informed health care is needed. Although those with food insecurity are at increased risk for poor pregnancy outcomes, they were less likely to have received adequate prenatal care despite high levels of public insurance coverage among study participants, suggesting additional strategies are needed to address barriers to health care among this population. Trial registration: The Outcomes of Babies with Opioid Exposure (OBOE) Study is registered at Clinical Trials.gov (NCT04149509) (04/11/2019).

The neonatal adverse event severity scale: current status, a stakeholders' assessment, and future perspectives.

To support informed decisions on drug registration and prescription, clinical trials need tools to assess the efficacy and safety signals related to a given therapeutic intervention. Standardized assessment facilitates reproducibility of results. Furthermore, it enables weighted comparison between different interventions, instrumental to facilitate shared decisions. When focused on adverse events in clinical trials, tools are needed to assess seriousness, causality and severity. As part of such a toolbox, the international Neonatal Consortium (INC) developed a first version of the neonatal adverse event severity scale (NAESS). This version underwent subsequent validation in retro-and prospective trials to assess its applicability and impact on the inter-observer variability. Regulators, sponsors and academic researchers also reported on the use of the NAESS in regulatory documents, trial protocols and study reports. In this paper, we aim to report on the trajectory, current status and impact of the NAESS score, on how stakeholders within INC assess its relevance, and on perspectives to further develop this tool.

Assessment of long-term neurodevelopmental outcome following trials of medicinal products in newborn infants.

There is significant uncertainty over the role of assessment of long-term neurodevelopmental outcome (LTO) in neonatal clinical trials. A multidisciplinary working group was established to identify key issues in this area and to make recommendations about optimal approaches to evaluate LTO in therapeutic trials in newborns, which can be developed by sponsors and investigators with other key stakeholders. A key consideration for neonatal trials is the potential for the investigational product to cause widespread effects and drives the need to assess outcome in multiple organs. Thus investigators must assess whether the product has an impact on the brain and the potential for it to cause potential effects on LTO. Critically, is assessment of LTO an important direct therapeutic target or a safety outcome? Such decisions and outcomes need to be specific to the product being studied and use published data, only considering expert opinion when prior evidence does not exist. In designing the trial, the balance of benefits, costs, and burdens of assessments to the researcher and families need to be considered. Families and parent advocates should be involved in design and execution of the study. A framework is presented for use by all key stakeholders to determine the need, nature, and duration of LTO assessments in regulatory trials involving newborn infants.

Impact of Regulatory Incentive Programs on the Future of Pediatric Drug Development.

Surveys evaluating industry experience with performing pediatric studies under the Best Pharmaceutical for Children Act (BPCA) and Pediatric Research Equity Act (PREA) regulatory regime were conducted by Tufts Center for the Study of Drug Development (Tufts CSDD) in 2000, 2006, and 2016. These survey results are being used to assess the future impact of regulatory incentive programs on generating pediatric specific labeling information and development of age-appropriate drug formulations. A second perspective will be provided through the experience and expertise of neonatal/pediatric clinicians and researchers with a focus on the urgent need for the study of new and existing drugs in this vulnerable population (especially with 90% of drugs in neonates still being used off-label). This group will also address the impact of existing regulations and the likely trajectory of future pediatric drug development efforts after nearly 2 decades of regulatory incentives (both mandatory and voluntary). Finally, this review will provide input on approaches that are needed to continue to advance pediatric drug development with an emphasis on rare diseases.

Pharmacologic treatment of infants with neonatal abstinence syndrome in community hospitals compared to academic medical centers.

OBJECTIVE: To compare length of hospital stay (LOS), LOS due to neonatal abstinence syndrome (NAS), and duration of pharmacologic treatment in community or academic settings. STUDY DESIGN: One hundred-two infants exposed to opioids in utero at two community hospitals were compared to 256 from eight academic centers. All infants were managed with non-pharmacologic care followed by similar pharmacologic treatment options. RESULTS: Two hundred-twelve infants received pharmacologic treatment for NAS. Mean LOS (24.7 ± 8.5 vs. 24.5 ± 11.3 days), LOS due to NAS (24.0 ± 8.2 vs. 23.3 ± 9.2 days), and duration of NAS treatment (19.3 ± 8.0 vs. 18.9 ± 9.2 days) were similar in community compared to academic medical centers. CONCLUSIONS: No significant differences were found in infants managed in the community compared to academic care settings. These findings support caring for opioid-exposed infants in both community and academic settings with the use of standardized care protocols.

Assessment of a shortened informed consent form for pediatric research: a pilot study.

BACKGROUND: Inherent to clinical research is the informed consent process, with the informed consent form (ICF), a key component of human participant protections. We wished to examine whether a shortened and simplified ICF, accompanied by an appendix, improved participant understanding of a study compared with a conventional ICF. METHODS: A shortened ICF was developed from an existing conventional ICF for a neonatal study. Either the shortened or conventional ICF was randomly distributed to members of two parental advocacy groups. Participants answered survey questions about the form they received. RESULTS: Thirty-one out of forty-one (76%) parents in the shortened ICF and 28/41 (68%) in the conventional ICF group responded. Significantly more parents in the shortened ICF group found their form "short and to the point". Although they also stated that the shortened ICF did not provide enough information, there were no significant differences between groups measuring the understanding of key study components. CONCLUSION: A shortened ICF did not impact the understanding of the clinical trial. It will be important to compare the shortened and conventional forms in actual clinical trials.

A Practical Approach to Neonatal Opiate Withdrawal Syndrome.

Perinatal opioid misuse and neonatal opioid withdrawal syndrome (NOWS) are a significant public health problem that has grown exponentially over the past decade. In the United States, a woman seeks emergency room care for prescription opioid misuse every 3 minutes and approximately every 25 minutes, a child is born with signs of drug withdrawal. The economic impact of perinatal opioid misuse is significant with annual hospital charges for NOWS in 2012 as $1.5 billion dollars. Perinatal opioid misuse is a complex, multifaceted problem that demands a multidisciplinary cross specialty approach. This article will review the current state of NOWS and provide medical practitioners with a practical guide to enhance evidence based practice.

Enrollment of Neonates in More Than One Clinical Trial.

Because the highest rates of morbidity and mortality in neonates are seen in those born at <32 weeks' gestation, this group has the most urgent need for novel therapies to improve survival and outcome. Legislative efforts in the United States and Europe have attempted to address this issue by requiring the study of drugs, biological and nutritional products, devices, and other therapies in this population through a combination of high-quality regulatory and clinical trials, quality improvement initiatives, and observational studies. Because there are relatively small numbers of very preterm neonates born each year in any 1 country or continent, and because a significant number of clinical trials are recruiting at any 1 time, a neonate may meet enrollment criteria for >1 clinical trial. Neonatal units that have the infrastructure and resources to engage in research frequently face the question of whether it is permissible to enroll a neonate in >1 trial. This article examines the pertinent scientific, ethical, regulatory, and industry issues that should be taken into account when considering enrolling neonates in multiple clinical studies.

Risk of neonatal drug withdrawal after intrauterine co-exposure to opioids and psychotropic medications: cohort study.

Objectives To assess the impact of in utero co-exposure to psychotropic medications and opioids on the incidence and severity of neonatal drug withdrawal.Design Observational cohort study.Setting Nationwide sample of pregnancies in publicly insured women in the US, nested in the Medicaid Analytic eXtract (2000-10).Participants 201 275 pregnant women with public insurance who were exposed to opioids around the time of delivery and their liveborn infants.Interventions In utero exposure to psychotropic medications, in particular antidepressants, atypical antipsychotics, benzodiazepines, gabapentin, and non-benzodiazepine hypnotics (Z drugs), with prescriptions filled within the same time window as prescriptions for opioids.Main outcome measure Diagnosis of neonatal drug withdrawal in infants exposed in utero to opioids and psychotropic medications compared with opioids alone.Results The absolute risk for neonatal drug withdrawal ranged from 1.0% in infants exposed in utero to prescription opioids alone to 11.4% for those exposed to opioids co-prescribed with gabapentin. Among neonates exposed in utero to prescription opioids, the relative risk adjusted for propensity score was 1.34 (95% confidence interval 1.22 to 1.47) with concomitant exposure to antidepressants, 1.49 (1.35 to 1.63) with benzodiazepines, 1.61 (1.26 to 2.06) with gabapentin, 1.20 (0.95 to 1.51) with antipsychotics, and 1.01 (0.88 to 1.15) with Z drugs. In utero exposure to two or more psychotropic medications along with opioids was associated with a twofold increased risk of withdrawal (2.05, 1.77 to 2.37). The severity of the withdrawal seemed increased in neonates exposed to both opioids and psychotropic medications compared with opioids alone.Conclusions During pregnancy, the use of psychotropic medications in addition to prescription opioids is common, despite a lack of safety data. The current findings suggest that these drugs could further increase the risk and severity of neonatal drug withdrawal.

Challenges and opportunities to enhance global drug development in neonates.

PURPOSE OF REVIEW: This study reviews the history of neonatal drug development, recent legislative efforts designed to facilitate the study of therapeutic agents in neonates, and future steps necessary to advance drug development. RECENT FINDINGS: Although many federal regulations have been introduced over the past 15 years to encourage pediatric and neonatal drug development, the majority of medications that are used in the Neonatal Intensive Care Unit are not approved by the Food and Drug Administration (FDA) for use in neonates. There are many challenges that investigators encounter in conducting neonatal clinical trials. The Critical Path Institute working in conjunction with the FDA has developed several consortia, including the International Neonatal Consortium and Pediatric Trials Consortium, to address these concerns and facilitate interactions of researchers, regulators, funding agencies, industry, and others across the globe to produce regulatory ready and high quality data for neonatal therapeutics. SUMMARY: Neonatal drug development is an area which deserves significant attention if we hope to continue to improve outcomes. With the help of international collaborations, it is possible to accelerate efficient and high quality neonatal research through multidisciplinary teams that share data, knowledge, and expertise to advance medical innovation and regulatory science.

Neonatal abstinence syndrome: Pharmacologic strategies for the mother and infant.

Opioid use in pregnancy has increased dramatically over the past decade. Since prenatal opioid use is associated with numerous obstetrical and neonatal complications, this now has become a major public health problem. In particular, in utero opioid exposure can result in neonatal abstinence syndrome (NAS) which is a serious condition characterized by central nervous system hyperirritability and autonomic nervous system dysfunction. The present review seeks to define current practices regarding the approach to the pregnant mother and neonate with prenatal opiate exposure. Although the cornerstone of prenatal management of opioid dependence is opioid maintenance therapy, the ideal agent has yet to be definitively established. Pharmacologic management of NAS is also highly variable and may include an opioid, barbiturate, and/or α-agonist. Genetic factors appear to be associated with the incidence and severity of NAS. Establishing pharmacogenetic risk factors for the development of NAS has the potential for creating opportunities for "personalized genomic medicine" and novel, individualized therapeutic interventions.

Meeting the demand for pediatric clinical trials.

High-quality, cost-effective pediatric clinical trials require a robust research and regulatory infrastructure and a properly trained workforce.

The CTSA mentored career development program: supporting the careers of child health investigators.

UNLABELLED: Training translational scientists is a priority of the Clinical and Translational Science Award (CTSA) consortium. OBJECTIVES: 1) Describe the landscape of CTSA Mentored Research Career Development Awards (CDA) and 2) evaluate participation and outcomes of child health investigators in these programs. DESIGN: Survey of the CTSA Child Health Oversight Committee (CC-CHOC) and review of nonresponders' CTSA Websites. RESULTS: Thirty-two of 53 CC-CHOC members (60%) responded and all nonresponder Websites were reviewed. Institutions supported 1,166 CDA positions from 2006 to 2011, with 134 awarded to child health investigators (11.5%). Respondents reported a mean of 29.8 KL2 positions (95% CI 17.5-42.2) during their award period, with a mean of 2.8 (95% CI 1.8-3.8) awarded to child health investigators. The proportion of child health awardees varied from 0% to 50% across institutions. We identified 45 subsequent National Institutes of Health (NIH) awards to the 134 child health investigators (34%). CONCLUSIONS: The CTSA program contributes substantially to training the next generation of translational investigators. One-third of child health investigators obtained subsequent NIH awards in the short follow-up period demonstrating success of the CTSA CDA programs. Child health investigators are represented variably across the consortium. Pediatric institutions can partner with the CTSA program to further support training child health investigators.

Reduced abuse, therapeutic errors, and diversion following reformulation of extended-release oxycodone in 2010.

UNLABELLED: This study evaluated changes in abuse exposures, therapeutic error exposures, and diversion into illegal markets associated with brand extended-release oxycodone (ERO) following introduction of reformulated ERO. Original ERO and reformulated ERO street prices also were compared. Data from the Poison Center and Drug Diversion programs of the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System were used. Quarterly rates 2 years prior to introduction of reformulated ERO (October 2008 through September 2010) were compared to quarterly rates after introduction (October 2010 through March 2012) using negative binomial regression. Street prices were compared using a mixed effects linear regression model. Following reformulated ERO introduction, poison center ERO abuse exposures declined 38% (95% confidence interval [CI]: 31-45) per population and 32% (95% CI: 24-39) per unique recipients of dispensed drug. Therapeutic error exposures declined 24% (95% CI: 15-31) per population and 15% (95% CI: 6-24) per unique recipients of dispensed drug. Diversion reports declined 53% (95% CI: 41-63) per population and 50% (95% CI: 39-59) per unique recipients of dispensed drug. Declines exceeded those observed for other prescription opioids in aggregate. After its introduction, the street price of reformulated ERO was significantly lower than original ERO. PERSPECTIVE: This article indicates that the abuse, therapeutic errors, and diversion of ERO declined following the introduction of a tamper-resistant reformulation of the product. Reformulating abused prescription opioids to include tamper-resistant properties may be an effective approach to reduce abuse of such products.