Clinically defining the opioid-exposed birthing person and infant as a dyad to support bedside care, surveillance, and research.

Introduction: An increased incidence of maternal opioid use disorder (OUD) and neonatal abstinence syndrome (NAS) has prompted recommendations supporting a dyadic approach to care for birthing persons and their infants. However, there are no consensus guidelines outlining how the dyad is clinically defined. Methods: To examine how the opioid-exposed birthing person-infant dyad has been defined for purposes of data collection and research, a literature review applying the RAND/UCLA Appropriateness Method was conducted. Results: The search yielded 320 abstracts, with 110 articles identified as having a dyadic focus. While no articles included a specific definition for the dyad, 33 (30%) contained a descriptive reference to the birthing person-infant dyad. Thematic analysis revealed eight recurring elements characteristic of the dyad: (1) engagement, (2) communication, (3) bonding, (4) attachment, (5) mutual responsiveness, (6) reciprocity, (7) synchrony, and (8) attunement. Integrating these elements revealed the interactional relationship between the opioid-exposed birthing person and infant as the foundational principle that defines the dyad. Discussion: This definition shifts the focus of the opioid-exposed dyad from two individual patient populations to an interactional relationship that has broad applicability for clinical use, public health data collection, and research considerations.

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).

Short term outcomes of neonatal opioid withdrawal syndrome: a comparison of two approaches.

OBJECTIVE: To evaluate outcomes in opioid exposed neonates (OENs) assessed by the Eat, Sleep, Console (ESC) tool compared to the Finnegan Neonatal Abstinence Scoring System (FNASS). METHODS: Retrospective analysis of a statewide database of OENs from 2017 to 2020 with birthing hospitals classified based on the assessment tool used. Four main outcomes were examined using multivariable and Poisson logistic regression models. RESULTS: Of 2375 OENs, 42.1% received pharmacotherapy (PT) with a consistent decrease in PT, length of treatment (LOT), and length of stay (LOS) over the study period. There was no change in use of mother's own milk (MoM). While outcomes were significantly associated with several specific variables, there were no differences in outcomes between assessment methods. CONCLUSION: While there was a significant decrease over time in PT, LOT, and LOS, improvements were independent of the assessment tool used and likely related to the increased use of non-pharmacologic care.

Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial.

Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial. Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia. Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023. Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period. Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup). Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit. Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.

First Trimester Use of Buprenorphine or Methadone and the Risk of Congenital Malformations.

Importance: Use of buprenorphine or methadone to treat opioid use disorder is recommended in pregnancy; however, their teratogenic potential is largely unknown. Objective: To compare the risk of congenital malformations following in utero exposure to buprenorphine vs methadone. Design, Setting, and Participants: This population-based cohort study used health care utilization data from publicly insured Medicaid beneficiaries in the US from 2000 to 2018. A total of 13 360 pregnancies with enrollment from 90 days prior to pregnancy start through 1 month after delivery and first trimester use of buprenorphine or methadone were included and linked to infants. Data were analyzed from July to December 2022. Exposure: A pharmacy dispensing of buprenorphine or a code for administration of methadone in the first trimester. Main Outcomes and Measures: Primary outcomes included major malformations overall and malformations previously associated with opioids (any cardiac malformations, ventricular septal defect, secundum atrial septal defect/nonprematurity-related patent foramen ovale, neural tube defects, clubfoot, and oral clefts). Secondary outcomes included other organ system-specific malformations. Risk differences and risk ratios (RRs) were estimated comparing buprenorphine with methadone, adjusting for confounders with propensity score overlap weights. Results: The cohort included 9514 pregnancies with first-trimester buprenorphine exposure (mean [SD] maternal age, 28.4 [4.6] years) and 3846 with methadone exposure (mean [SD] maternal age, 28.8 [4.7] years). The risk of malformations overall was 50.9 (95% CI, 46.5-55.3) per 1000 pregnancies for buprenorphine and 60.6 (95% CI, 53.0-68.1) per 1000 pregnancies for methadone. After confounding adjustment, buprenorphine was associated with a lower risk of malformations compared with methadone (RR, 0.82; 95% CI, 0.69-0.97). Risk was lower with buprenorphine for cardiac malformations (RR, 0.63; 95% CI, 0.47-0.85), including both ventricular septal defect (RR, 0.62; 95% CI, 0.39-0.98) and secundum atrial septal defect/nonprematurity-related patent foramen ovale (RR, 0.54; 95% CI, 0.30-0.97), oral clefts (RR, 0.65; 95% CI, 0.35-1.19), and clubfoot (RR, 0.55; 95% CI, 0.32-0.94). Results for neural tube defects were uncertain given low event counts. In secondary analyses, buprenorphine was associated with a decreased risk of central nervous system, urinary, and limb malformations but a greater risk of gastrointestinal malformations compared with methadone. These findings were consistent in sensitivity and bias analyses. Conclusions and Relevance: In this cohort study, the risk of most malformations previously associated with opioid exposure was lower in buprenorphine-exposed infants compared with methadone-exposed infants, independent of measured confounders. Malformation risk is one factor that informs the individualized patient decision regarding medications for opioid use disorder in pregnancy.

Psychological distress among postpartum women who took opioids during pregnancy: the role of perceived stigma in healthcare settings.

This study examined the relationship between perceived stigma in healthcare settings during pregnancy and psychological distress and well-being in the postpartum period among individuals who took opioids while pregnant. Analyses included 134 birth mothers of opioid-exposed infants. At 0-1 months postpartum, perceived stigma and psychological distress were measured using the Prenatal Opioid use Perceived Stigma scale and measures from the Patient-Reported Outcome Measurement Information System (PROMIS). Food insecurity, housing instability, and Adverse Childhood Experiences (ACEs) were also assessed. Linear and generalized linear mixed-effect models were conducted to compare PROMIS scale scores and unmet needs by stigma, adjusting for site/location, age, race/ethnicity, marital status, education, public insurance, and parity. More than half of participants (54%) perceived stigma in healthcare settings. Individuals reporting stigma had higher depression, anxiety, and anger scores (p < 0.001) indicating greater psychological distress in the postpartum period compared to those reporting no stigma, after controlling for demographic characteristics. In addition, they scored significantly lower on the PROMIS meaning and purpose scale, an indicator of well-being (p = 0.002). Those reporting stigma were more likely to have food insecurity (p = 0.003), three or more ACEs (p = 0.040), verbal or physical abuse during pregnancy (p < 0.001), and less emotional support (p = 0.006) than those who did not. An association was observed between perceived stigma in the prenatal period and psychological distress in the postpartum period, providing support for stigma reduction interventions and education for healthcare providers on trauma-informed care.

A Dyadic Framework of Care for Opioid-exposed Birthing Persons and Their Infants and Children.

OBJECTIVE: To develop a dyadic-centered framework focused on clinical care, surveillance, and research for birthing persons with opioid use disorder (OUD) and their infants and children. STUDY DESIGN: Between February and March 2023, an analysis was conducted within the US Department of Health and Human Services (HHS) of activities directed at opioid-exposed birthing persons and their infants and children (the dyad) to identify: 1) number of activities, stratified by type and 2) characteristics across health and supportive activities that serve the dyad vs birthing persons or infants and children individually. Descriptive and thematic analyses were used to assess quantity and characteristics of fiscal year 2023-2024 activities aggregated across eleven HHS agencies. RESULTS: Of 181 activities examined, 75 met inclusion criteria specific to serving birthing persons with OUD and opioid-exposed infants and children. Sixty-two percent of activities were dyad focused. Five categories of dyadic activities were identified: research (45%), education and training (28%), health and supportive services (21%), surveillance (4%), and quality improvement (2%). Eight specific characteristics were key to dyadic activities: a life course and generational approach, emphasis on relationship, dyadic outcomes, service wraparound, payment structures supporting dyadic care, data linkage, and social determinants of health. CONCLUSIONS: This analysis of HHS activities directed at birthing persons with OUD and opioid-exposed infants and children showed that most programs had a dyadic focus. Synthesizing elements identified from activities serving the dyad facilitated the development of a dyadic framework integrating clinical care, public health surveillance, and research.

Neonatal Survival After Serial Amnioinfusions for Bilateral Renal Agenesis: The Renal Anhydramnios Fetal Therapy Trial.

Importance: Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival. Objective: To assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks' gestation to mitigate lethal pulmonary hypoplasia. Design, Setting, and Participants: Prospective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies. Exposure: Enrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks' gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age. Main Outcomes and Measures: The primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement. Results: The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks' gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks). Conclusions and Relevance: Serial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden. Trial Registration: ClinicalTrials.gov Identifier: NCT03101891.

Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder.

Importance: Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results. Objective: To compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test. Design, Setting, and Participants: The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a prospective, comparative, multicenter study of 400 hospitalized infants younger than 1 year of age (proband) and their parents, when available, suspected of having a genetic disorder. The study was conducted at 6 US hospitals from June 2019 to November 2021. Exposure: Enrolled participants underwent simultaneous testing with genomic sequencing and a targeted neonatal gene-sequencing test. Each laboratory performed an independent interpretation of variants guided by knowledge of the patient's phenotype and returned results to the clinical care team. Change in clinical management, therapies offered, and redirection of care was provided to families based on genetic findings from either platform. Main Outcomes and Measures: Primary end points were molecular diagnostic yield (participants with ≥1 pathogenic variant or variant of unknown significance), time to return of results, and clinical utility (changes in patient care). Results: A molecular diagnostic variant was identified in 51% of participants (n = 204; 297 variants identified with 134 being novel). Molecular diagnostic yield of genomic sequencing was 49% (95% CI, 44%-54%) vs 27% (95% CI, 23%-32%) with the targeted gene-sequencing test. Genomic sequencing did not report 19 variants found by the targeted neonatal gene-sequencing test; the targeted gene-sequencing test did not report 164 variants identified by genomic sequencing as diagnostic. Variants unidentified by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar odds ratio, 8.6 [95% CI, 5.4-14.7]). Variant interpretation by laboratories differed by 43%. Median time to return of results was 6.1 days for genomic sequencing and 4.2 days for the targeted genomic-sequencing test; for urgent cases (n = 107) the time was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test. Changes in clinical care affected 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in clinical decision-making, irrespective of a diagnosis. Conclusions and Relevance: The molecular diagnostic yield for genomic sequencing was higher than a targeted neonatal gene-sequencing test, but the time to return of routine results was slower. Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management.

A review of the genomics of neonatal abstinence syndrome.

Neonatal abstinence syndrome (NAS) is a constellation of signs of withdrawal occurring after birth following in utero exposure to licit or illicit opioids. Despite significant research and public health efforts, NAS remains challenging to diagnose, predict, and manage due to highly variable expression. Biomarker discovery in the field of NAS is crucial for stratifying risk, allocating resources, monitoring longitudinal outcomes, and identifying novel therapeutics. There is considerable interest in identifying important genetic and epigenetic markers of NAS severity and outcome that can guide medical decision making, research efforts, and public policy. A number of recent studies have suggested that genetic and epigenetic changes are associated with NAS severity, including evidence of neurodevelopmental instability. This review will provide an overview of the role of genetics and epigenetics in short and longer-term NAS outcomes. We will also describe novel research efforts using polygenic risk scores for NAS risk stratification and salivary gene expression to understand neurobehavioral modulation. Finally, emerging research focused on neuroinflammation from prenatal opioid exposure may elucidate novel mechanisms that could lead to development of future novel therapeutics.

The state and future of pediatric research-an introductory overview : The state and future of pediatric research series.

IMPACT: This is an introduction to an article series devoted to the current state and future of pediatric research. The role of public-private partnerships, influencing factors, challenges, and recent trends in pediatric research are described, with emphasis on funding, drug and device development, physician-scientist training, and diversity. Potential solutions and advocacy opportunities are discussed.

Establishing a global regulatory floor for children's decisions about participation in clinical research.

BACKGROUND: Enrolling children in clinical trials typically requires parental or guardian permission and, when appropriate, child assent. Aligning requirements across jurisdictions would facilitate multisite pediatric trials. Guidance from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is the best candidate for a global standard but would benefit from additional specification. METHODS: Ethical analysis of ICH guidance for permission and assent for pediatric trials, with recommendations for clarification. RESULTS: ICH guidance regarding permission and assent would be enhanced by additional detail in the following areas: (1) what information should be provided to parents, guardians, and children considering a trial, and how that information should be provided; (2) the definition of "assent," the criteria for when assent should be required, and the need to include children in discussions even when assent is not mandated; (3) criteria for requiring children's signatures indicating agreement; (4) greater specificity regarding children's right to decline or withdraw; and (5) clarification of when children's wish to decline or withdraw from participation may be overridden and of what the overriding process should entail. CONCLUSION: ICH guidance provides a global standard for decision making regarding children's participation in trials. Several clarifications would facilitate the conduct of multinational pediatric research. IMPACT: Enrolling children in clinical trials requires the permission of a parent/guardian ± the assent of the minor. Differing global regulatory requirements for enrolling children complicate the conduct of multicenter and multinational trials. The authors identify points of ambiguity and/or contradiction in the International Council for Harmonization guidelines and offer recommendations for a common ethical platform for conducting global pediatric research.

Psychometric Properties of the Prenatal Opioid Use Perceived Stigma Scale and Its Use in Prenatal Care.

OBJECTIVE: To examine the psychometric properties of the Prenatal Opioid Use Perceived Stigma (POPS) scale and to assess the relationship of POPS scores to adequate prenatal care. DESIGN: Prospective cohort study. SETTING: Medical centers in Alabama, Ohio, and Pennsylvania (N = 4). PARTICIPANTS: Women (N = 127) who took opioids during pregnancy and whose infants participated in the Outcomes of Babies With Opioid Exposure Study. METHODS: Participants reported their perceptions of stigma during pregnancy by responding to the eight items on the POPS scale. We evaluated the instrument's internal consistency reliability (Cronbach's alpha), structural validity (factor analysis), and convergent validity (relationship with measures of similar constructs). In addition, to assess construct validity, we used logistic regression to examine the relationship of POPS scores to the receipt of adequate prenatal care. RESULTS: The internal consistency of the POPS scale was high (Cronbach's α = .88), and all item-total correlations were greater than 0.50. The factor analysis confirmed that the items cluster into one factor. Participants who reported greater perceived stigma toward substance users and everyday discrimination in medical settings had higher POPS scores, which supported the convergent validity of the scale. POPS scores were significantly associated with not receiving adequate prenatal care, adjusted OR = 1.47, 95% confidence interval [1.19, 1.83], p < .001. CONCLUSION: The psychometric testing of the POPS scale provided initial support for the reliability and validity of the instrument. It may be a useful tool with which to assess perceived stigma among women who take opioids, a potential barrier to seeking health care during pregnancy.

Protection of Two and Three mRNA Vaccine Doses Against Severe Outcomes Among Adults Hospitalized With COVID-19-VISION Network, August 2021 to March 2022.

BACKGROUND: We assessed coronavirus disease 2019 (COVID-19) vaccination impact on illness severity among adults hospitalized with COVID-19, August 2021-March 2022. METHODS: We evaluated differences in intensive care unit (ICU) admission, in-hospital death, and length of stay among vaccinated (2 or 3 mRNA vaccine doses) versus unvaccinated patients aged ≥18 years hospitalized for ≥24 hours with COVID-19-like illness and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) molecular testing. We calculated odds ratios (ORs) for ICU admission and death and subdistribution hazard ratios (SHR) for time to hospital discharge adjusted for age, geographic region, calendar time, and local virus circulation. RESULTS: We included 27 149 SARS-CoV-2-positive hospitalizations. During both Delta- and Omicron-predominant periods, protection against ICU admission was strongest among 3-dose vaccinees compared with unvaccinated patients (Delta OR, 0.52 [95% CI, .28-.96]; Omicron OR, 0.69 [95% CI, .54-.87]). During both periods, risk of in-hospital death was lower among vaccinated compared with unvaccinated patients but ORs overlapped across vaccination strata. We observed SHR >1 across all vaccination strata in both periods indicating faster discharge for vaccinated patients. CONCLUSIONS: COVID-19 vaccination was associated with lower rates of ICU admission and in-hospital death in both Delta and Omicron periods compared with being unvaccinated.

Sex-specific inflammatory and white matter effects of prenatal opioid exposure: a pilot study.

BACKGROUND: Preclinical data demonstrate that opioids modulate brain reward signaling through an inflammatory cascade, but this relationship has yet to be studied in opioid-exposed neonates. METHODS: Saliva samples of 54 opioid-exposed and sex- and age-matched non-exposed neonates underwent transcriptomic analysis of inflammatory and reward genes. A subset of 22 neonates underwent brain magnetic resonance imaging (MRI) to evaluate white matter injury commonly associated with inflammatory response. Gene expression and brain MRI were compared between opioid- and non-exposed neonates and further stratified by sex and pharmacotherapy need. RESULTS: Opioid-exposed females regardless of pharmacotherapy need had higher expression of inflammatory genes than their male counterparts, with notable differences in the expression of CCL2 and CXCL1 in females requiring pharmacotherapy (p = 0.01 and 0.06, respectively). Opioid-exposed males requiring pharmacotherapy had higher expression of DRD2 than exposed females (p = 0.07), validating our prior research. Higher expression of IL1ß, IL6, TNFα, and IL10 was seen in opioid-exposed neonates with T1 white matter hyperintensity (WMH) compared to exposed neonates without WMH (p < 0.05). CONCLUSION: Prenatal opioid exposure may promote inflammation resulting in changes in reward signaling and white matter injury in the developing brain, with unique sex-specific effects. The actions of opioids through non-neuronal pathways need further investigation. IMPACT: Opioid-exposed neonates are at risk for punctate T1 white matter hyperintensity (WMH). Females carry a greater propensity for WMH. Salivary transcriptomic data showed significantly higher expression of inflammatory genes in opioid-exposed neonates with WMH than those without WMH, irrespective of pharmacotherapy need. Adding to prior studies, our findings suggest that prenatal opioid exposure may modulate white matter injury and reward signaling through a pro-inflammatory process that is sex specific. This novel study highlights the short-term molecular and structural effects of prenatal opioids and the need to elucidate the long-term impact of prenatal opioid exposure.

Polygenic risk scores and the need for pharmacotherapy in neonatal abstinence syndrome.

BACKGROUND: The aim of this study was to identify genetic variants associated with NAS through a genome-wide association study (GWAS) and estimate a Polygenic Risk Score (PRS) model for NAS. METHODS: A prospective case-control study included 476 in utero opioid-exposed term neonates. A GWAS of 1000 genomes-imputed genotypes was performed to identify variants associated with need for pharmacotherapy for NAS. PRS models for estimating genetic predisposition were generated via a nested cross-validation approach using 382 neonates of European ancestry. PRS predictive ability, discrimination, and calibration were assessed. RESULTS: Cross-ancestry GWAS identified one intergenic locus on chromosome 7 downstream of SNX13 exhibiting genome-wide association with need for pharmacotherapy. PRS models derived from the GWAS for a subset of the European ancestry neonates reliably discriminated between need for pharmacotherapy using cis variant effect sizes within validation sets of European and African American ancestry neonates. PRS were less effective when applying variant effect sizes across datasets and in calibration analyses. CONCLUSIONS: GWAS has the potential to identify genetic loci associated with need for pharmacotherapy for NAS and enable development of clinically predictive PRS models. Larger GWAS with additional ancestries are needed to confirm the observed SNX13 association and the accuracy of PRS in NAS risk prediction models. IMPACT: Genetic associations appear to be important in neonatal abstinence syndrome. This is the first genome-wide association in neonates with neonatal abstinence syndrome. Polygenic risk scores can be developed examining single-nucleotide polymorphisms across the entire genome. Polygenic risk scores were higher in neonates receiving pharmacotherapy for treatment of their neonatal abstinence syndrome. Future studies with larger cohorts are needed to better delineate these genetic associations.