Neonatal opioid toxicity: opioid withdrawal (abstinence) syndrome with emphasis on pharmacogenomics and respiratory depression.

The increasing use of opioids in pregnant women has led to an alarming rise in the number of cases of neonates with drug-induced withdrawal symptoms known as neonatal opioid withdrawal syndrome (NOWS). NOWS is a toxic heterogeneous condition with many neurologic, autonomic, and gastrointestinal symptoms including poor feeding, irritability, tachycardia, hypertension, respiratory defects, tremors, hyperthermia, and weight loss. Paradoxically, for the management of NOWS, low doses of morphine, methadone, or buprenorphine are administered. NOWS is a polygenic disorder supported by studies of genomic variation in opioid-related genes. Single-nucleotide polymorphisms (SNPs) in CYP2B6 are associated with variations in NOWS infant responses to methadone and SNPs in the OPRM1, ABCB1, and COMT genes are associated with need for treatment and length of hospital stay. Epigenetic gene changes showing higher methylation levels in infants and mothers have been associated with more pharmacologic treatment in the case of newborns, and for mothers, longer infant hospital stays. Respiratory disturbances associated with NOWS are not well characterized. Little is known about the effects of opioids on developing neonatal respiratory control and respiratory distress (RD), a potential problem for survival of the neonate. In a rat model to test the effect of maternal opioids on the developing respiratory network and neonatal breathing, maternal-derived methadone increased apneas and lessened RD in neonates at postnatal (P) days P0 and P1. From P3, breathing normalized with age suggesting reorganization of respiratory rhythm-generating circuits at a time when the preBötC becomes the dominant inspiratory rhythm generator. In medullary slices containing the preBötC, maternal opioid treatment plus exposure to exogenous opioids showed respiratory activity was maintained in younger but not older neonates. Thus, maternal opioids blunt centrally controlled respiratory frequency responses to exogenous opioids in an age-dependent manner. In the absence of maternal opioid treatment, exogenous opioids abolished burst frequencies at all ages. Prenatal opioid exposure in children stunts growth rate and development while studies of behavior and cognitive ability reveal poor performances. In adults, high rates of attention deficit disorder, hyperactivity, substance abuse, and poor performances in intelligence and memory tests have been reported.

"Will My Baby Be OK?" A Qualitative Analysis of Pregnant Women's Suboxone® Online Forum Posts.

BACKGROUND: Intentional or accidental drug-overdose is a leading cause of mortality in U.S. women of child-bearing age. Opioid use during pregnancy is not only associated with maternal overdose, but with low birth weight at term and neonatal abstinence syndrome (NAS). Buprenorphine was approved as a medication for opioid use disorder (MOUD) in the United States in 2002 and is for many women, a preferred treatment option versus methadone. Buprenorphine is relatively safe during pregnancy and is associated with lower rates of NAS than methadone. Given the importance of MOUD during pregnancy, relatively little information exists regarding patients' questions and concerns about buprenorphine treatment, including the psychological challenges they face. AIMS: The purpose of the study was to describe the perinatal concerns of women with opioid use disorder who posted to an online suboxone forum. METHODS: Qualitative descriptive design to analyze some 170 posts from mothers with OUD to an online Suboxone® support forum over the period 2016-2021. RESULTS: The analysis of the interview data revealed 4 important themes: (a) Stigma resulting in self-deprecation, low self-esteem, and low self-efficacy; (b) stigma from family members and loved ones; (c) stigma from the medical profession; and (d) stigma from the community at-large (social stigma). CONCLUSIONS: There is compelling evidence to emphasize the importance of open communication and support between medical personnel and patients to ensure optimal outcomes for mother and baby.

Drug testing in support of the diagnosis of neonatal abstinence syndrome: The current situation.

Illicit drug use during pregnancy is a concern worldwide, with many international studies describing attempted strategies to mitigate this problem. Drug misuse during pregnancy is associated with significant maternal as well as perinatal complications, which include a high incidence of stillbirths, fetal distress, neonatal abstinence syndrome (NAS) and increased neonatal mortality. Unfortunately, the identification of a drug-exposed mother or neonate is challenging. Maternal disclosure of drug use is often inaccurate, principally due to psychosocial factors including behavioral denial or the fear of the consequences resulting from such admissions. Likewise, many infants who have been exposed to drugs in utero may appear normal at birth and initially show no overt manifestations of drug effects. Thus, the identification of the drug-exposed infant requires a high index of clinical suspicion. Conversely, analytical testing is an objective means of determining drug exposure when it may be necessary to document proof of the infant's exposure to illicit drugs. The review will discuss the different matrices that are most commonly used for testing (e.g., maternal urine, neonatal urine, meconium, and umbilical cord), the strengths and limitations for each matrix, which drugs and metabolites are appropriate for testing, the various testing methods, and the advantages and disadvantages of each method.

The placenta as a target of opioid drugs†.

Opioid drugs are analgesics increasingly being prescribed to control pain associated with a wide range of causes. Usage of pregnant women has dramatically increased in the past decades. Neonates born to these women are at risk for neonatal abstinence syndrome (also referred to as neonatal opioid withdrawal syndrome). Negative birth outcomes linked with maternal opioid use disorder include compromised fetal growth, premature birth, reduced birthweight, and congenital defects. Such infants require lengthier hospital stays necessitating rising health care costs, and they are at greater risk for neurobehavioral and other diseases. Thus, it is essential to understand the genesis of such disorders. As the primary communication organ between mother and conceptus, the placenta itself is susceptible to opioid effects but may be key to understanding how these drugs affect long-term offspring health and potential avenue to prevent later diseases. In this review, we will consider the evidence that placental responses are regulated through an endogenous opioid system. However, maternal consumption of opioid drugs can also bind and act through opioid receptors express by trophoblast cells of the placenta. Thus, we will also discuss the current human and rodent studies that have examined the effects of opioids on the placenta. These drugs might affect placental hormones associated with maternal recognition of pregnancy, including placental lactogens and human chorionic gonadotropin in rodents and humans, respectively. A further understanding of how such drugs affect the placenta may open up new avenues for early diagnostic and remediation approaches.

A Meta-Analysis of Breastfeeding Effects for Infants With Neonatal Abstinence Syndrome.

BACKGROUND: Neonatal abstinence syndrome (NAS) rates have dramatically increased. Breastfeeding is a nonpharmacological intervention that may be beneficial, reducing NAS symptom severity and thus the need for and duration of pharmacological treatment and length of hospital stay. OBJECTIVES: Conduct meta-analysis to determine whether breastfeeding results in better outcomes for NAS infants. Variables included symptom severity, need for and duration of pharmacological treatment, and length of hospital stay. METHODS: PubMed, Scopus, Embase, and Cochrane Library were searched from 2000 to 2020, and comparative studies examining breastfeeding for NAS infants were extracted. Randomized trials and cohort studies were included. Data were extracted and evaluated with Review Manager Version 5.3. A random-effects model was used to pool discontinuous outcomes using risk ratio and 95% confidence intervals. Continuous outcomes were evaluated by mean differences and 95% confidence intervals. RESULTS: Across 11 studies, 6,375 neonates were included in the meta-analysis. Using a random-effects analysis, breastfeeding reduced initiation of pharmacological treatment, reduced duration of pharmacological treatment, and reduced length of stay. No differences were detected for severity of NAS symptoms. Most studies only reported one to two variables of interest. For most studies, these variables were not the primary study outcomes. All studies were found to be of low risk and good quality based on the Cochrane Risk Assessment Tools. Varying breastfeeding definitions limit generalizability. DISCUSSION: Breastfeeding is associated with decreased initiation and duration of pharmacological treatment and length of stay.

Opioids and the developing brain: time to rethink perinatal care for infants of opioid-dependent mothers.

Illicit use of opioids is a global health crisis with major implications for women and children. Strategies for managing opioid use disorder (OUD) in pregnancy have been tested over the past 40 years, but studies have focused on maternal and pregnancy outcomes, with less attention given to long-term follow-up of exposed children. Here, we provide a narrative review of recent advances in the assessment and management of neonatal opioid withdrawal syndrome (NOWS), and we summarise evidence from multiple domains-neuroimaging, electrophysiology, visual development and function, neurodevelopment, behaviour, cognition and education-which suggests that prenatal opioid exposure modifies child development. Further studies are required to determine the optimal management of pregnant women with OUD and babies with NOWS. We identify knowledge gaps and suggest that future study designs should evaluate childhood outcomes, including infant brain development and long-term neurocognitive and visual function.

Maternal opioid use disorder: Placental transcriptome analysis for neonatal opioid withdrawal syndrome.

Excessive prenatal opioid exposure may lead to the development of Neonatal Opioid Withdrawal Syndrome (NOWS). RNA-seq was done on 64 formalin-fixed paraffin-embedded placental tissue samples from 32 mothers with opioid use disorder, with newborns with NOWS that required treatment, and 32 prenatally unexposed controls. We identified 93 differentially expressed genes in the placentas of infants with NOWS compared to unexposed controls. There were 4 up- and 89 downregulated genes. Among these, 7 genes CYP1A1, APOB, RPH3A, NRXN1, LINC01206, AL157396.1, UNC80 achieved an FDR p-value of <0.01. The remaining 87 genes were significant with FDR p-value <0.05. The 4 upregulated, CYP1A1, FP671120.3, RAD1, RN7SL856P, and the 10 most significantly downregulated genes were RNA5SP364, GRIN2A, UNC5D, DMBT1P1, MIR3976HG, LINC02199, LINC02822, PANTR1, AC012178.1, CTNNA2. Ingenuity Pathway Analysis identified the 7 most likely to play an important role in the etiology of NOWS. Our study expands insights into the genetic mechanisms of NOWS development.

Developmental Outcomes of Children Born with Neonatal Abstinence Syndrome (NAS): A Scoping Review.

AIMS: The purpose of this scoping review is to provide an overview of developmental outcomes of children diagnosed with neonatal abstinence syndrome (NAS). METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework was used to guide this scoping review. A comprehensive search of CINAHL, MEDLINE, EMBASE, Web of Science, and PsycINFO was conducted using search terms related to NAS and developmental areas. Full-text screening was completed for 30 articles, and eight studies were included in this review. RESULTS: Cognitive and language development, as well as school performance, social and motor domains, may be areas of concern in children with NAS. CONCLUSIONS: The developmental outcomes of infants with NAS cannot be firmly determined due to inconsistent results across reviewed studies. Future research investigating development across various ages is required for rending more appropriate intervention services to this high-risk population.

Feeding Behaviors in Infants With Prenatal Opioid Exposure: An Integrative Review.

BACKGROUND: Oral feeding is one of the most complex maturational skills of infancy. Difficulties with feeding require specialized attention, and if not well managed, may prolong the newborn's hospital length of stay. This is particularly true for prenatally opioid exposed (POE) infants. A paucity of literature exists characterizing feeding behaviors of POE infants, yet feeding problems are common. PURPOSE: The purpose of this integrative review was to synthesize and critically analyze the evidence that characterizes feeding behaviors in full-term, POE infants. METHODS/SEARCH STRATEGY: The electronic databases of CINAHL, PubMed, Scopus, and PsycINFO were used. Inclusion criteria were studies in English, conducted from 1970 to 2019, with participant samples consisting of infants with prenatal opioid exposure, born full-term, and between 38 and 40 weeks of gestation. Based on the inclusion criteria, our search yielded 557 articles. After further screening, only 4 studies met our full inclusion/exclusion criteria. These studies were analyzed for evidence of infant feeding behaviors, including characterization of problematic feeding behavior for POE infants. FINDINGS/RESULTS: Our findings revealed inconsistencies in characterization of feeding behaviors among POE infants. A synthesis of the most common evidence-based behaviors was constructed. Infant feeding behaviors were identified and grouped into 2 major behavior domains: (1) typical feeding behavior and (2) problematic feeding behavior. IMPLICATIONS FOR PRACTICE AND RESEARCH: Feeding behaviors related to sucking and behavioral states may be different in POE infants. Further examination of effective assessment methods and the categorization of infant feeding behaviors are warranted for use in the development of evidence-based, targeted intervention.

Childhood Health and Educational Outcomes After Neonatal Abstinence Syndrome: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically review and meta-analyze the association between neonatal abstinence syndrome (NAS) and adverse health or educational childhood outcomes. STUDY DESIGN: An all-language search was conducted across 11 databases between January 1, 1975, and September 3, 2019; 5865 titles were identified. Observational studies of children between 28 days and 16 years of age, in whom a diagnosis of NAS was documented, were included. Outcomes included reasons for hospital admissions, childhood diagnoses, developmental outcomes, and academic attainment scores. All studies underwent independent review by 2 trained reviewers, who extracted study data and assessed risk of bias using the Newcastle Ottawa Tool. RESULTS: Fifteen studies were identified that included 10 907 children with previous NAS and 1 730 213 children without previous NAS, aged 0-16 years. There was a strong association between NAS and subsequent child maltreatment (aOR, 6.49; 95% CI, 4.46-9.45; I2 = 52%), injuries and poisoning (aOR, 1.34; 95% CI, 1.21-1.49; I2 = 0%), and a variety of mental health conditions. Studies consistently demonstrated an increased incidence of strabismus and nystagmus among those with previous NAS. Children with NAS also had lower mean academic scores than the control group in every domain of testing across age groups. CONCLUSIONS: NAS is significantly associated with future child maltreatment, mental health diagnoses, visual problems, and poor school performance. Owing to the necessary inclusion of nonrandomized studies, incomplete reporting among studies, and likely unadjusted confounding, this review does not suggest causation. However, we highlight associations requiring further investigation and targeted intervention, to positively impact the life course trajectories of this growing population of children.

Integrative Review of Gut Microbiota and Expression of Symptoms Associated With Neonatal Abstinence Syndrome.

BACKGROUND: Neonatal exposure and subsequent withdrawal from maternal substance use disorder are a growing problem and consequence of the current opioid epidemic. Neonatal abstinence syndrome (NAS) is defined by a specified cluster of symptoms with treatment guided by the expression and severity of these symptoms. The mechanisms or pathophysiology contributing to the development of NAS symptoms are not well known, but one factor that may influence NAS symptoms is the gut microbiota. OBJECTIVES: The purpose of this integrative review was to examine evidence that might show if and how the gut microbiota influence expression and severity of symptoms similar to those seen in NAS. METHODS: Using published guidelines, a review of research studies that focused on the gut microbiome and symptoms similar to those seen in NAS was conducted, using the Cochrane, EMBASE, and Scopus databases, from 2009 through 2019. RESULTS: The review results included findings of aberrant microbial diversity, differences in microbial communities between study groups, and associations between specific taxa and symptoms. In studies involving interventions, there were reports of improved microbial diversity, community structure, and symptoms. DISCUSSION: The review findings provide evidence that the gut microbiota may play a role in modifying variability in the expression and severity of symptoms associated with NAS. Future research should focus on examining the gut microbiota in infants with and without the syndrome as well as exploring the relationship between symptom expression and aberrant gut microbiota colonization in infants with NAS.

The Effects of Neonatal Abstinence Syndrome on Language Delay from Birth to 10 Years.

PURPOSE: To examine the longitudinal effects of a history of neonatal abstinence syndrome (NAS) on language development over the first 10 years of life. DESIGN AND METHODS: This study used a retrospective, longitudinal design. The data were analyzed using generalized linear mixed models (GLMM) to examine the effects of NAS on language delay over time while controlling for demographic, prenatal, and household factors. RESULTS: There was a significant difference in the pattern of language delays over time between the NAS and non-NAS groups. At the age of 5 (est: -1.788, p < .001), children with a history of NAS had a decreased log odds of developing language delays than those without NAS. Conversely, compared with age 1, at the age of 10 (est: 1.098 p < .001), children with a history of NAS had an increased log odds of developing language delays than those without NAS. CONCLUSIONS: Children with a history of NAS had significantly different rates of language delays over time. Children with a history of NAS had significantly higher rates of language delays at 10 years than children without NAS. PRACTICE IMPLICATIONS: There is a need to increase developmental surveillance, along with referrals for specialized services, for children with a history of NAS through middle childhood.

The Association of Concomitant Maternal Marijuana Use on Health Outcomes for Opioid Exposed Newborns in Massachusetts, 2003-2009.

This population-based study showed that maternal opioid plus marijuana use during pregnancy was associated with increased odds of prematurity and low birth weight but lower odds of neonatal abstinence syndrome and prolonged hospitalization compared with opioid exposure without marijuana use. Further research should evaluate the biologic mechanisms responsible for these outcomes.

Sex-Dependent Gene Expression in Infants with Neonatal Opioid Withdrawal Syndrome.

OBJECTIVES: To evaluate salivary biomarkers that elucidate the molecular mechanisms by which in utero opioid exposure exerts sex-specific effects on select hypothalamic and reward genes driving hyperphagia, a hallmark symptom of infants suffering from neonatal opioid withdrawal syndrome (NOWS). STUDY DESIGN: We prospectively collected saliva from 50 newborns born at ≥34 weeks of gestational age with prenatal opioid exposure and 50 sex- and gestational age-matched infants without exposure. Saliva underwent transcriptomic analysis for 4 select genes involved in homeostatic and hedonic feeding regulation (neuropeptide Y2 receptor [NPY2R], proopiomelanocortin [POMC], leptin receptor [LEPR], dopamine type 2 receptor [DRD2]). Normalized gene expression data were stratified based on sex and correlated with feeding volume on day of life 7 and length of stay in infants with NOWS requiring pharmacotherapy. RESULTS: Expression of DRD2, a hedonistic/reward regulator, was significantly higher in male newborns compared with female newborns with NOWS (Δ threshold cycle 10.8 ± 3.8 vs 13.9 ± 3.7, P = .01). In NOWS requiring pharmacotherapy expression of leptin receptor, an appetite suppressor, was higher in male subjects than female subjects (Δ threshold cycle 8.4 ± 2.5 vs 12.4 ± 5.1, P = .05), DRD2 expression significantly correlated with intake volume on day of life 7 (r = 0.58, P = .02), and expression of NPY2R, an appetite regulator, negatively correlated with length of stay (r = -0.24, P = .05). CONCLUSIONS: Prenatal opioid exposure exerts sex-dependent effects on hypothalamic feeding regulatory genes with clinical correlations. Neonatal salivary gene expression analyses may predict hyperphagia, severity of withdrawal state, and length of stay in infants with NOWS.

Prenatal Opioid Exposure: Neurodevelopmental Consequences and Future Research Priorities.

Neonatal opioid withdrawal syndrome (NOWS) has risen in prevalence from 1.2 per 1000 births in 2000 to 5.8 per 1000 births in 2012. Symptoms in neonates may include high-pitched cry, tremors, feeding difficulty, hypertonia, watery stools, and breathing problems. However, little is known about the neurodevelopmental consequences of prenatal opioid exposure in infancy, early childhood, and middle childhood. Even less is known about the cognitive, behavioral, and academic outcomes of children who develop NOWS. We review the state of the literature on the neurodevelopmental consequences of prenatal opioid exposure with a particular focus on studies in which NOWS outcomes were examined. Aiming to reduce the incidence of prenatal opioid exposure in the near future, we highlight the need for large studies with prospectively recruited participants and longitudinal designs, taking into account confounding factors such as socioeconomic status, institutional variations in care, and maternal use of other substances, to independently assess the full impact of NOWS. As a more immediate solution, we provide an agenda for future research that leverages the National Institutes of Health Environmental Influences on Child Health Outcomes program to address many of the serious methodologic gaps in the literature, and we answer key questions regarding the short- and long-term neurodevelopmental health of children with prenatal opioid exposure.

Moral distress of nurses surrounding neonatal abstinence syndrome: Application of a theoretical framework.

TOPIC: Neonatal nurses who care for infants with symptoms of neonatal abstinence syndrome (NAS) may experience moral distress through conflicting professional ethics. The nurse may find it difficult to simultaneously exemplify beneficence and nonmaleficence. OBJECTIVE: The purpose of this paper is to explore the moral distress of nurses in the context of infants experiencing symptoms of NAS and apply a new conceptual model to this phenomenon. Understanding how nurses navigate moral dilemmas may provide insight into strategies to better support them to address moral conflict. METHODS: Moral distress was explored in the context of nurses who care for infants with symptoms of NAS. A literature review was completed, followed by the application of the model onto the derived themes. RESULTS: The theoretical application resulted in a framework that exemplifies the experience of caring for infants with symptoms of NAS and their families described by many nurses within the literature. If moral distress is not resolved, negative outcomes may be experienced by the nurse, with additional negative outcomes experienced by the family. CONCLUSION: This theoretical model provided insight into the experience of moral distress surrounding nursing care for infants with symptoms of NAS. Additional research is needed to investigate moral residue and moral resilience in this particular caregiving dynamic.

Developmental Disorders and Medical Complications Among Infants with Subclinical Intrauterine Opioid Exposures.

The objective was to compare diagnosis rates representing developmental outcomes and medical complications between infants with intrauterine opioid exposures who did not receive pharmacologic treatment for neonatal abstinence syndrome at the time of birth and infants for whom no exposure to substances of abuse were detected. This retrospective, descriptive study included approximately 95% of Hamilton County, Ohio resident births in 2014 and 2015. Universal maternal drug test results, performed at the time of birth, were documented and linked to electronic health records representing pediatric primary and subspecialty follow-up care as well as urgent care, emergency care, and inpatient services provided by Cincinnati Children's Hospital Medical Center through 2017, when all children were at least 24 months old. Diagnosis rates were compared between drug exposure groups using chi-square tests. Among infants born at >34 weeks gestation and without other complex clinical conditions, infants with subclinical opioid exposures (N = 473) were more likely than infants with no drug exposures (N = 14,933) to be diagnosed with behavioral or emotional disorders (3.0% vs 1.1%, P = 0.0008), developmental delay (15.6% vs 7.6%, P < 0.0001), speech disorder (10.1% vs 6.5%, P = 0.001), or strabismus (3.4% vs 1.0%, P < 0.0001), and more likely to be exposed to the hepatitis C virus (6.8% vs 0.1%, P < 0.0001). Increased diagnosis rates among all opioid exposed infants, regardless of withdrawal severity, may warrant the additional allocation of resources for screening and follow-up. Awareness of the increased risk for certain developmental delays and medical conditions is critical to early intervention and treatment supporting improved outcomes.

Parent's experiences of their child's withdrawal syndrome: a driver for reciprocal nurse-parent partnership in withdrawal assessment.

Withdrawal assessment in critically ill children is complicated by the reliance on non-specific behaviours and compounded when the child's typical behaviours are unknown. The existing approach to withdrawal assessment assumes that nurses elicit the parents' view of the child's behaviours. OBJECTIVE AND RESEARCH METHODOLOGY: This qualitative study explored parents' perspectives of their child's withdrawal and preferences for involvement and participation in withdrawal assessment. Parents of eleven children were interviewed after their child had completed sedation weaning during recovery from critical illness. Data were analysed using thematic analysis. SETTING: A large children's hospital in the Northwest of England. FINDINGS: Parents experienced varying degrees of partnership in the context of withdrawal assessment and identified information deficits which contributed to their distress of parenting a child with withdrawal syndrome. Most parents were eager to participate in withdrawal assessment and reported instances where their knowledge enabled a personalised interpretation of their child's behaviours. Reflecting on the reciprocal nature of the information deficits resulted in the development of a model for nurse-parent collaboration in withdrawal assessment. CONCLUSION: Facilitating nurse-parent collaboration in withdrawal assessment may have reciprocal benefits by moderating parental stress and aiding the assessment and management of withdrawal syndrome.

Neonatal Head Circumference in Newborns With Neonatal Abstinence Syndrome.

OBJECTIVES: To compare head circumference (HC) in neonates treated for neonatal abstinence syndrome (NAS) with control neonates without antenatal opioid exposure. METHODS: Our prospective cohort study ran from April 1, 2014, through December 31, 2016. Newborns treated for NAS delivered from well-dated pregnancies ≥34 weeks' gestation were compared with newborns who were nonopioid exposed and matched for race, parity, mode of delivery, and gestational age. All mothers underwent serial antenatal urine drug testing. A minimum of 754 study participants were needed (377 in each group) to demonstrate an increase in the proportion of newborns with HCs less than or equal to the 10th percentile from 10% in controls to a minimum of 20% in NAS newborns with 90% power. RESULTS: A total of 858 neonates were enrolled (429 NAS cases and 429 controls). Mean HC for cases was 33.04 cm (±1.9 cm) compared with 33.99 cm (±2.0 cm) for controls (P < .0001). Among the 429 NAS cases, the mothers of 372 (87%) were on opioid medication-assisted treatment. For NAS cases, 30.1% (95% confidence interval: 25.8%-34.7%) had an HC less than or equal to the 10th percentile (129 of 429 neonates), and 8.2% (95% confidence interval: 5.8%-11.2%) had an HC less than or equal to the third percentile (35 of 429 neonates). Multivariate analysis was used and determined that only chronic opioid use during gestation resulting in a neonate who was NAS treated was a significant risk factor for the observed smaller HC. CONCLUSIONS: Chronic opioid use during pregnancy sufficient to cause NAS was associated with smaller HCs at birth. Most mothers were on opioid agonist medication-assisted treatment, which is currently the recommended treatment option during pregnancy.