Association between NNNS-II Profiles and Pharmacological Treatment in Infants with Prenatal Opioid Exposure

Association between NNNS-II Profiles and Pharmacological Treatment in Infants with Prenatal Opioid Exposure | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Association between NNNS-II Profiles and Pharmacological Treatment in Infants with Prenatal Opioid Exposure Barry Lester, Macie Donahue, Madison Ramirez Heil, Marie Camerota, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8099613/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Mar, 2026 Read the published version in Journal of Perinatology → Version 1 posted 9 You are reading this latest preprint version Abstract Objective: Examine whether neonatal neurobehavioral profiles are related to need for pharmacological treatment among infants with prenatal opioid exposure. Study Design: Prospective cohort study of 217 infants with need for treatment determined using the Finnegan Neonatal Abstinence Tool (FNAST), Neonatal Withdrawal Inventory (NWI), or Eat Sleep Console (ESC). Neurobehavior was assessed with the NeoNatal Neurobehavioral Scale II (NNNS-II). Latent Profile Analysis (LPA) classified infants into neurobehavioral profiles and logistic regression assessed the association between NNNS-II profiles and need for treatment. Results: A 3-profile LPA solution best fit the NNNS-II data comprised of typical (67%), hyper-aroused (19%) and hypo-aroused groups (15%). Infants with atypical NNNS-II profiles were more likely to receive treatment (OR=3.45, 95% CI 1.21-9.81) compared to infants with typical profiles ( p < .05, Table 4). Conclusion: Newborn neurobehavioral profiles may aid in early identification of infants requiring pharmacological treatment for opioid withdrawal, reducing length of stay and healthcare costs. Health sciences/Health care/Paediatrics Health sciences/Health care/Diagnosis/Physical examination Figures Figure 1 Figure 2 Introduction Neonatal opioid withdrawal syndrome (NOWS) is characterized by dysregulation of the central, autonomic, and gastrointestinal systems in some newborns with prenatal opioid exposure [ 1 ]. Symptoms of NOWS include a range of clinical signs including high pitched cries, increased muscle tone, tremors, poor feeding, and poor sleep [ 2 , 3 ]. From 2010 to 2017, both the rate of maternal opioid-related diagnoses and the incidence of NOWS increased nationally [ 5 – 7 ]. Maternal opioid-related disorders increased from 3.5 to 8.2 per 1,000 delivery hospitalizations and the rate of NOWS increased from 4.0 to 7.3 per 1,000 birth hospitalizations [ 6 ]. The clinical presentation of NOWS varies depending on factors such as opioid type, maternal drug history, and maternal and infant metabolism [ 4 ]. Some infants exhibit only mild symptoms of NOWS, while others experience more severe symptoms requiring pharmacological treatments. Typical hospital practices involve continuous monitoring of infants’ withdrawal symptoms for 3 to 7 days after birth, a practice that is costly and can impact care [ 4 ]. First-line treatment for NOWS typically includes non-pharmacological interventions which promote mother-infant bonding, including maternal rooming-in, skin-to-skin contact, and a low stimulation environment with reduced noise and light [ 2 , 8 ]. For infants exceeding predefined symptom thresholds as measured by NOWS assessment tools, pharmacological treatments such as morphine are used to manage NOWS symptoms [ 9 ]. As not all infants with prenatal opioid exposure will require medication, this extended observation period may not be necessary for all infants. Few predictive models are available for determining the onset and severity of NOWS. Of the existing models, none have demonstrated the performance necessary for clinical implementation [ 10 , 11 ]. The NICU Network Neurobehavioral Scale (NNNS), the precursor to the NeoNatal Neurobehavioral Scale II (NNNS-II), has been used extensively in neonatal populations with prenatal opioid exposures [ 12 – 16 ]. The NNNS was developed as part of the Maternal Lifestyle Study to study the effects of prenatal drug exposure, including opiates, on child outcomes [ 17 ]. Prior studies using the NNNS have identified neurodevelopmental profiles that describe subgroups of neonates with similar neurobehavioral patterns, or combinations of NNNS summary scores [ 12 – 15 ]. Atypical NNNS profiles have been related to long-term neurodevelopmental outcomes in infants with prenatal opioid exposure [ 14 , 15 ] . The NNNS-II, administered in this study, is a comprehensive, standardized newborn neurobehavioral assessment. Recent studies using the NNNS-II have shown that neonates with prenatal opioid exposure have distinctive patterns of neurobehavior and that the NNNS-II may predict NOWS severity prior to clinical signs of NOWS [ 18 , 19 ]. It has yet to be shown whether newborn neurobehavior, especially neurobehavioral profiles, is associated with the need for pharmacological treatment for infants with prenatal opioid exposure. Predicting the need for treatment prior to meeting NOWS symptom thresholds is significant as it could allow for shorter hospital stays, enable infants requiring medication to start treatment sooner, and lead to reduced healthcare costs. The objective of this study was to test whether neonatal neurobehavior in the first two days after birth is associated with the need for pharmacological treatment in infants with prenatal opioid exposure. Methods Participants Participants were part of the Child and Family Study, a prospective multi-site study seeking to identify novel clinical predictors of NOWS. 217 mother-infant dyads with prenatal opioid exposure were recruited from prenatal clinics and postnatally at Women and Infant’s Hospital of Rhode Island and University of Utah Hospital between 2019 and 2025. Mothers were approached for consent if prenatal opioid use was identified during pregnancy or at delivery via maternal medical record, a positive maternal urine toxicology during pregnancy or at hospital admission, and/or a positive infant umbilical or urine toxicology screen after birth. Newborns were excluded if they had congenital anomalies, genetic syndromes, metabolic disturbances, sepsis, asphyxia, seizures, respiratory failure, gestational age < 33 weeks, were medically unstable for the NNNS-II exam, unable to take oral medications, or if their caregiver was unable to provide informed consent. Study procedures were approved by the Institutional Review Board of each study site and all participants provided written informed consent for their participation. Measures NeoNatal Neurobehavioral Scale – II (NNNS-II) Trained examiners administered the NNNS-II exam to assess neonatal neurobehavior within 24–48 hours after birth, prior to NOWS treatment. The NNNS-II is a revised and shortened version of the original NNNS exam—a comprehensive standardized evaluation of newborn neurobehavioral performance highlighting neurobehavioral regulation, reflexes, tone and signs of stress and abstinence in the neonate [ 17 ]. In the NNNS-II, the original NNNS summary scales were refined and items were retained that statistically contributed to the sensitivity and specificity of the exam. The NNNS-II yields 8 summary scores: attention, handling, self-regulation, arousal, tone, non-optimal reflexes, quality of movement, and stress abstinence. The 15-minute exam was conducted in the infant’s room or in a semi-private room in the nursery. NOWS Treatment Information about NOWS symptom assessment and pharmacological treatment was abstracted from the infant’s medical record. Initiation of pharmacological treatment for NOWS was based on hospital practices at each site. Women and Infants Hospital used the Finnegan Neonatal Abstinence Scoring Tool (FNAST) [ 20 ]. University of Utah Hospital used Neonatal Withdrawal Inventory (NWI) and Eat Sleep Console (ESC) [ 21 , 22 ]. Infants were assessed every 2–4 hours. The FNAST is arguably the most widely used, quantifiable NOWS assessment tool. Criteria for initiating pharmacological treatment consisted of 3 consecutive scores greater than 7 or 2 consecutive scores greater than 11. The NWI is an 8-item, empirical measure of infant withdrawal derived from the FNAST. Treatment was initiated when the infant received one or more scores of 8 or higher. The ESC tool is a newer assessment focusing on vital infant functions such as eating and sleeping. Criteria for initiating pharmacological treatment were: inability for the infant to eat the appropriate amount based on age, sleep undisturbed for a minimum of 1 hour in between care times, and/or be consoled within 10 minutes [ 23 ]. To account for variability in rates of pharmacological treatment based on these different assessments, we adjusted for study site in the analysis. Statistical Analysis Maternal substance use and maternal and infant characteristics were examined in infants treated versus those not treated for NOWS. Means and standard deviations were used for continuous measures. Categorical variables are expressed as observed counts and percentages. Significance levels for differences between treated and not treated infants were derived from one-way Analysis of Variance (ANOVA) and chi-square tests for continuous and categorical variables, respectively. Latent profile analysis (LPA) was used to classify infants into mutually exclusive neurobehavioral groups based on the 8 NNNS-II summary scores. LPA models with different numbers of profiles were fit and the model containing the optimal number of profiles was identified. Determination of the best model fit was assessed via Bayesian information criteria (BIC) with the smallest BIC value indicating the best fit as well as higher entropy, non-significant bootstrapped likelihood ratio tests and a sufficient number of cases in each profile (> 5% of the sample). Missing data were handled using full information maximum likelihood. To determine if NNNS-II summary scores and NNNS-II profiles were associated with the need for pharmacological treatment, we conducted logistic regression models with treatment as the dependent variable. Adjusted logistic regression models additionally controlled for study site. Results Descriptive Statistics 217 mother and newborn dyads from Utah (n = 90) and Rhode Island (n = 127) were enrolled. Of those, 135 had an NNNS-II exam prior to becoming symptomatic for NOWS and are included in this analysis. Symptomatic was defined as at least one score of an 8 or higher on the FNAST or NWI, or any yes on the ESC. Figure 1 outlines participant flow from initial contact through enrollment to inclusion in this analysis. For this analysis, participants were divided into two groups: those receiving pharmacological treatment ( n = 37) and those that did not ( n = 98). Descriptive maternal and infant characteristics, separated by treatment group, are described in Tables 1 and 2 . Of note, the mean number of opioids mothers used did not differ between the treatment and no treatment groups (2.2 v 2.1, p = 0.67). Polysubstance use (e.g., marijuana, tobacco, and stimulants) was more common in the treatment group (Table 2 ). 65% of the infants who required treatment had DCYF involvement as compared to 36% in the no treatment group ( p = 0.002). Additionally, fewer infants in the treatment group (48.6% v 69.4%, p = 0.025) were breastfed. Of the 135 participants, 74 received FNAST, 21 received NWI, 24 received ESC, and 16 infants in Utah did not receive a NOWS assessment. None of the infants lacking a NOWS assessment received pharmacological treatment. Table 1 Maternal and Infant Characteristics by Infant Pharmacological Treatment Group Treatment (N = 37) No treatment (N = 98) p-value M (SD) or N (%) M (SD) or N (%) Maternal Characteristics Less than high school degree 7 (19.4%) 24 (25.8%) 0.448 Adequate prenatal care 28 (75.7%) 79 (81.4%) 0.457 No partner 20 (54.1%) 42 (43.3%) 0.264 Hypertension 6 (16.2%) 19 (19.4%) 0.672 Residential Treatment 8 (21.6%) 20 (20.4) 0.877 Inpatient detox during pregnancy 8 (25.0%) 17 (19.1%) 0.480 Bipolar 12 (32.45) 18 (18.8%) 0.091 PTSD 14 (37.8%) 32 (33.3%) 0.625 Hepatitis C 15 (41.7%) 29 (30.5%) 0.228 Infant Characteristics Sex (Male) 15 (40.5%) 52 (53.1%) 0.194 Gestational Age (weeks) 38.6 (1.3) 38.1 (1.7) 0.132 Birth Weight (grams) 2899 (547) 3014 (546) 0.236 Head circumference at birth (cm) 33.3 (2.0) 33.7 (1.9) 0.291 Length at birth (inches) 47.9 (3.0) 48.5 (2.6) 0.237 DCYF Involvement 24 (64.9%) 35 (35.7%) 0.002 Breastfeeding 18 (48.6%) 68 (69.4%) 0.025 Maximum Finnegan Score 11.6 (1.9) 7.7 (1.9) < 0.001 Note . PTSD = post-traumatic stress disorder; DCYF = Department of Children, Youth, and Families Table 2 Maternal Substance Use by Infant Pharmacological Treatment Group Treatment (N = 37) No treatment (N = 98) p-value M (SD) or N (%) M (SD) or N (%) Opioids Number of opioids 2.2 (1.5) 2.1 (1.3) 0.673 Fentanyl 17 (45.9%) 27 (28.1%) 0.050 Buprenorphine 25 (67.6%) 56 (58.3%) 0.328 Methadone 13 (35.1%) 32 (33.3%) 0.844 Heroin 12 (32.4%) 28 (29.2%) 0.713 Morphine 7 (18.9%) 19 (19.8%) 0.909 Oxycodone 4 (10.8%) 19 (19.8%) 0.308 Any illicit opioid 24 (64.9%) 58 (59.2%) 0.547 Other substances Alcohol 5 (13.5%) 11 (11.2%) 0.714 Marijuana 20 (54.1%) 29 (29.6%) 0.008 Nicotine 34 (91.9%) 66 (67.3%) 0.004 Any stimulant 37 (100%) 74 (75.5%) < 0.001 Any benzodiazepines 14 (37.8%) 18 (18.4%) 0.018 Any anti-anxiety 22 (59.5%) 43 (44.8%) 0.129 Any anti-depressants 20 (54.1%) 40 (41.7%) 0.198 Any antipsychotic 10 (27.0%) 18 (18.8%) 0.294 NNNS-II and NOWS Treatment We fit LPA models with increasing number of profiles to determine the optimal solution. Based on our selection criteria, the 3-profile solution best fit the NNNS-II data with fit statistics shown in Table 3 . Model entropy and average class probabilities were highest for the 3-profile solution and the 4-profile solution failed to converge. Profile 1 included 20 subjects (15%, Fig. 2 ). These infants showed the lowest attention and regulation, hypotonia, and non-optimal reflexes and were classified as hypo-aroused. Profile 2 comprised of 90 subjects (67%). These infants displayed average NNNS-II scores and were labeled as showing typical neurobehavior. Profile 3 included 25 subjects (19%). This group showed high arousal and stress along with poor quality of movement and were classified as hyper-aroused. Table 3 Model Fit Statistics for LPA Models Number of Profiles Convergence Problems Lowest LLH Replicated BIC Entropy Smallest Class Size LMRT p -value BLRT p -value 1 No Yes 2987.13 -- -- -- -- 2 No Yes 2976.85 0.677 60 (44%) 0.277 < 0.0001 3 No Yes 2992.55 0.842 20 (15%) 0.137 0.0128 4 Yes -- -- -- -- -- -- Note: BIC sample size-adjusted Bayesian Information Criterion, BLRT bootstrapped likelihood ratio test, LLH log likelihood, LMRT Lo–Mendell–Rubin test, LPA latent profile analysis. Convergence problems were noted when the majority of solutions failed to converge. Infants with an atypical NNNS-II profile (either hyper- or hypo-aroused) were more likely to receive pharmacological treatment for NOWS (OR = 3.45, 95% CI 1.21–9.81) compared to infants with the typical profile ( p < .05, Table 4 ). Examining individual summary scores, we found that infants with greater non-optimal reflexes were more likely to receive pharmacological treatment for NOWS (OR = 1.55, 95% CI 1.00-2.40) and infants with increased signs of stress and abstinence were also more likely to receive treatment (OR = 3.11, 95% CI 1.16–8.33, all p’s < .05). Conversely, infants with better quality of movement were less likely to receive treatment (OR = 0.53, 95% CI 0.33–0.84, p < .05). Table 4 NNNS-II Summary Scores and Profiles by Treatment Treatment (N = 37) No treatment (N = 98) Unadjusted OR (95% CI) Adjusted OR (95% CI) NNNS-II Summary Scores Attention 3.8 (0.9) 4.0 (1.3) 0.89 (0.57, 1.37) 0.84 (0.52, 1.35) Handling 4.7 (1.8) 4.7 (1.8) 0.99 (0.79, 1.25) 1.06 (0.83, 1.36) Self-Regulation 4.4 (1.0) 4.4 (1.2) 0.98 (0.69, 1.40) 0.79 (0.52, 1.21) Arousal 5.1 (2.0) 5.2 (1.6) 0.97 (0.78, 1.21) 1.04 (0.82, 1.33) Tone 5.2 (0.9) 4.9 (0.7) 1.63 (0.95, 2.77) 1.44 (0.82, 2.54) Non-optimal Reflexes 4.0 (1.1) 3.8 (1.0) 1.21 (0.82, 1.78) 1.55 (1.001, 2.40) Quality of Movement 5.8 (1.0) 6.2 (0.9) 0.60 (0.39, 0.93) 0.53 (0.33, 0.84) Stress Abstinence 2.1 (0.4) 1.9 (0.4) 2.87 (1.11, 7.39) 3.11 (1.16, 8.33) NNNS-II Profiles Hyper/Hypo 15 (40.5%) 30 (30.6%) 1.55 (0.71, 3.39) 3.45 (1.21, 9.81) Typical 22 (59.5%) 68 (69.4%) - - Note: Adjusted OR come from models adjusted for study site. OR = odds ratio, CI = confidence interval, NNNS-II = NeoNatal Neurobehavioral Scale II Discussion The overall goal of this study was to investigate whether neonatal neurobehavioral profiles as assessed by the NNNS-II within the first two days of life were associated with the need for pharmacological treatment in infants with prenatal opioid exposure. We found that infants could be classified into one of three distinct phenotypes, a hyper-aroused profile, a typical profile, and a hypo-aroused profile (Fig. 2 ). Atypical NNNS-II profiles, which included infants that were either hyper- or hypo-aroused, were more likely to require pharmacological treatment for NOWS symptoms. Analysis of NNNS-II summary scores showed that infants with non-optimal reflexes and increased signs of stress and abstinence were more likely to receive pharmacological treatment whereas infants with better quality of movement were less likely to receive treatment. These findings reveal the importance and potential clinical utility of neonatal neurobehavioral phenotypes when predicting the need for pharmacological treatment in infants with prenatal opioid exposure. NOWS severity and clinical presentation is highly variable and impacted by factors such as polysubstance use, postnatal feeding (e.g., breastfeeding vs formula), and complex social dynamics, consistent with the differences we found between the treatment and no treatment groups [ 24 – 26 ]. Additionally, our study confirms previous findings that infants with more signs of stress and abstinence on the NNNS are more likely to require pharmacological treatment than those who do not [ 27 ]. Furthermore, recent studies using the NNNS-II have shown that the NNNS-II summary scores may be associated with NOWS severity including the infant’s length of treatment and number of pharmacological medications required [ 19 ]. The Finnegan scoring items have also been shown to be significantly correlated with the NNNS items indicating that the NNNS can be used to supplement existing tools for identification of infants at risk for NOWS [ 28 ]. When evaluating infants at risk for NOWS, it is important to consider the whole child. The NNNS-II profiles presented in this study are a holistic characterization of the child’s neurobehavioral repertoire and may have value in shaping the approach to care for infants at risk for NOWS. Neonatal neurobehavioral profiles have previously been studied in various clinical populations including infants born preterm and infants with prenatal opioid exposure to identify groups of infants with similar neurobehavioral characteristics [ 13 – 15 , 18 , 29 ]. Profiles provide a way of looking at the whole child with clearer clinical cutoffs as compared to summary scores alone. The two dysregulated profiles seen in this study, hyper- and hypo-aroused, have been previously identified using the NNNS in a study of both term and pre-term infants with different perinatal exposures [ 29 ]. In a study of infants with prenatal methadone exposure, infants were classified into four profiles. Infants in profile 4 were characterized by the highest arousal, excitability, hypertonicity, non-optimal reflexes and stress abstinence and those in profile 1 exhibited the lowest attention and highest lethargy [ 30 ]. Beyond these populations, similar NNNS phenotypes are evident in low-risk infants with no prenatal substance exposure or other risks for neurobehavioral deficits [ 31 ]. Thus, the atypical hyper- and hypo-aroused profiles are commonly observed phenotypes in neonatal populations. In children with prenatal opioid exposure, atypical NNNS profiles have been associated with a greater likelihood of receiving higher doses of treatment drugs (morphine or methadone), in addition to predicting infant behavioral and developmental outcomes [ 13 – 15 ]. However, these studies used the original version of the NNNS exam. More recently, NNNS-II profiles have been used to compare the neurobehavior of infants with and without prenatal opioid exposure revealing that infants with prenatal exposure to opioids and other psychotropic substances have distinctive patterns of neurobehavior. Four NNNS-II profiles were identified with profile 4 most closely resembling a hyper-aroused phenotype; infants in this profile were more likely to have prenatal opioid exposure compared to those in other profiles [ 18 ]. The present study builds upon the prior findings and is the first to show that NNNS-II profiles are associated with the need for pharmacological treatment in infants with prenatal opioid exposure. The findings of our study in conjunction with the current literature emphasize the clinical utility of the NNNS-II exam when caring for and assessing infants at risk for NOWS. These findings should be interpreted considering the following limitations. Due to a small sample size, the two atypical NNNS-II profiles were grouped together for analysis despite their opposing neurobehavioral characteristics. Future studies with a larger sample size will allow for analysis of the hyper- and hypo-aroused infants separately and therefore could provide improved clinical guidance for these vulnerable infants. Additionally, our cohort includes three different NOWS assessments which play a direct role in infants’ treatment outcomes. However, this is representative of the variability in medical approaches to evaluate and care for infants with prenatal opioid exposure across the U.S. [ 32 , 33 ]. It is notable that the NNNS-II was associated with the need for pharmacological treatment in our study sample despite the difference in clinical practices across sites. Conclusion In conclusion, neonatal neurobehavior is associated with the need for pharmacological treatment in infants with prenatal opioid exposure. Information about NNNS-II profiles could be used to contribute to an innovative predictive model for determining whether infants with prenatal opioid exposure will require pharmacological treatment for NOWS. Early identification of those infants at risk for more severe NOWS symptoms could enable earlier treatment, potentially reducing length of stay and associated healthcare costs. Additionally, given that studies using the original NNNS have shown predictive validity of NNNS profiles for downstream developmental outcomes and delays, if our profiles are similar, we can hypothesize that infants with atypical profiles will have similar developmental challenges. Further research is needed to understand the predictive properties of each atypical profile, along with the effect of opioid type and other measures of NOWS severity when predicting treatment outcomes. Declarations Acknowledgments: We are grateful to our study staff and the infants and their caregivers who made this study possible. Author Contributions: BL and EC conceptualized and designed the study and critically reviewed and revised the manuscript for important intellectual content. MD and MC contributed to manuscript conceptualization. MD and MRH performed data collection and prepared the initial draft of the manuscript. LD and MC carried out the statistical analyses. All authors critically reviewed, edited, and finalized the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. Funding: All phases of this study were supported by the National Institute of Drug Abuse: R01DA049755 Competing Interests: The authors have no competing interests relevant to this article to disclose. Ethics Approval and Consent to Participate: Study procedures were approved by the Institutional Review Board (IRB) of each study site and all participants provided written informed consent for their participation. All methods were performed in accordance with relevant guidelines and regulations. References Logan BA, Brown MS, Hayes MJ. Neonatal Abstinence Syndrome: Treatment and Pediatric Outcomes. Clin Obstet Gynecol. 2013;56(1):186–92. Kraft WK, Stover MW, Davis JM. Neonatal abstinence syndrome: Pharmacologic strategies for the mother and infant. Semin Perinatol. 2016;40(3):203–12. 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Neonatal Opioid Withdrawal Syndrome (NOWS): A Transgenerational Echo of the Opioid Crisis. Cold Spring Harb Perspect Med. 2021;11(3):a039669. Additional Declarations There is NO conflict of interest to disclose. Cite Share Download PDF Status: Published Journal Publication published 20 Mar, 2026 Read the published version in Journal of Perinatology → Version 1 posted Editorial decision: revise 25 Nov, 2025 Review # 2 received at journal 24 Nov, 2025 Reviewer # 2 agreed at journal 18 Nov, 2025 Review # 1 received at journal 17 Nov, 2025 Reviewer # 1 agreed at journal 14 Nov, 2025 Reviewers invited by journal 14 Nov, 2025 Submission checks completed at journal 13 Nov, 2025 Editor assigned by journal 12 Nov, 2025 First submitted to journal 12 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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University","correspondingAuthor":false,"prefix":"","firstName":"Macie","middleName":"","lastName":"Donahue","suffix":""},{"id":545201582,"identity":"5d031503-df18-4890-9313-e4927d64400c","order_by":2,"name":"Madison Ramirez Heil","email":"","orcid":"","institution":"Warren Alpert Medical School of Brown University","correspondingAuthor":false,"prefix":"","firstName":"Madison","middleName":"Ramirez","lastName":"Heil","suffix":""},{"id":545201583,"identity":"6d94edda-9b51-487f-9c66-a96e2eea4dcf","order_by":3,"name":"Marie Camerota","email":"","orcid":"","institution":"Warren Alpert Medical School of Brown University","correspondingAuthor":false,"prefix":"","firstName":"Marie","middleName":"","lastName":"Camerota","suffix":""},{"id":545201584,"identity":"30bb7808-015b-488d-a135-4019e2b749bb","order_by":4,"name":"Lynne Dansereau","email":"","orcid":"","institution":"Brown Alpert Medical School and Women and Infants Hospital, 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09:08:42","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":109958,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8099613/v1/fce6417e6c0f3725f2a9e95f.html"},{"id":96804665,"identity":"6e82f3df-ede2-4cc9-b5b4-6d2795c4bff8","added_by":"auto","created_at":"2025-11-26 09:08:46","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":42182,"visible":true,"origin":"","legend":"\u003cp\u003eScreening, Eligibility, and NNNS-II Sample Size Consort Diagram. This outlines participant flow from initial contact through enrollment to inclusion in this analysis.\u003c/p\u003e","description":"","filename":"ScreeningEligibilityandNNNSIISampleSize.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8099613/v1/ed315be814e3e98ed78648c2.jpg"},{"id":96804727,"identity":"a0279625-4e96-4182-8a19-a10f829adf13","added_by":"auto","created_at":"2025-11-26 09:08:48","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":48596,"visible":true,"origin":"","legend":"\u003cp\u003eNNNS-II Summary Scores by Latent Profile. LPA analysis yielded three profiles: hyper-aroused (N=25, dashed blue line), hypo-aroused (N=20, dotted green line), and typical (N=25, solid purple line).\u003c/p\u003e","description":"","filename":"NNNSIISummaryScoresbyLatentProfile.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8099613/v1/4b80b6348c97a4c7af3c62c2.jpg"},{"id":105101959,"identity":"a3d02c90-d67f-41d4-ba71-2d732ef94880","added_by":"auto","created_at":"2026-03-21 07:11:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":896965,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8099613/v1/40f78c6f-5aaa-481c-a310-e9051578967b.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Association between NNNS-II Profiles and Pharmacological Treatment in Infants with Prenatal Opioid Exposure","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeonatal opioid withdrawal syndrome (NOWS) is characterized by dysregulation of the central, autonomic, and gastrointestinal systems in some newborns with prenatal opioid exposure [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Symptoms of NOWS include a range of clinical signs including high pitched cries, increased muscle tone, tremors, poor feeding, and poor sleep [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. From 2010 to 2017, both the rate of maternal opioid-related diagnoses and the incidence of NOWS increased nationally [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Maternal opioid-related disorders increased from 3.5 to 8.2 per 1,000 delivery hospitalizations and the rate of NOWS increased from 4.0 to 7.3 per 1,000 birth hospitalizations [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The clinical presentation of NOWS varies depending on factors such as opioid type, maternal drug history, and maternal and infant metabolism [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Some infants exhibit only mild symptoms of NOWS, while others experience more severe symptoms requiring pharmacological treatments.\u003c/p\u003e\u003cp\u003eTypical hospital practices involve continuous monitoring of infants\u0026rsquo; withdrawal symptoms for 3 to 7 days after birth, a practice that is costly and can impact care [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. First-line treatment for NOWS typically includes non-pharmacological interventions which promote mother-infant bonding, including maternal rooming-in, skin-to-skin contact, and a low stimulation environment with reduced noise and light [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. For infants exceeding predefined symptom thresholds as measured by NOWS assessment tools, pharmacological treatments such as morphine are used to manage NOWS symptoms [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. As not all infants with prenatal opioid exposure will require medication, this extended observation period may not be necessary for all infants.\u003c/p\u003e\u003cp\u003eFew predictive models are available for determining the onset and severity of NOWS. Of the existing models, none have demonstrated the performance necessary for clinical implementation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The NICU Network Neurobehavioral Scale (NNNS), the precursor to the NeoNatal Neurobehavioral Scale II (NNNS-II), has been used extensively in neonatal populations with prenatal opioid exposures [\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The NNNS was developed as part of the Maternal Lifestyle Study to study the effects of prenatal drug exposure, including opiates, on child outcomes [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Prior studies using the NNNS have identified neurodevelopmental profiles that describe subgroups of neonates with similar neurobehavioral patterns, or combinations of NNNS summary scores [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Atypical NNNS profiles have been related to long-term neurodevelopmental outcomes in infants with prenatal opioid exposure [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] .\u003c/p\u003e\u003cp\u003eThe NNNS-II, administered in this study, is a comprehensive, standardized newborn neurobehavioral assessment. Recent studies using the NNNS-II have shown that neonates with prenatal opioid exposure have distinctive patterns of neurobehavior and that the NNNS-II may predict NOWS severity prior to clinical signs of NOWS [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. It has yet to be shown whether newborn neurobehavior, especially neurobehavioral profiles, is associated with the need for pharmacological treatment for infants with prenatal opioid exposure. Predicting the need for treatment prior to meeting NOWS symptom thresholds is significant as it could allow for shorter hospital stays, enable infants requiring medication to start treatment sooner, and lead to reduced healthcare costs. The objective of this study was to test whether neonatal neurobehavior in the first two days after birth is associated with the need for pharmacological treatment in infants with prenatal opioid exposure.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eParticipants\u003c/h2\u003e\u003cp\u003eParticipants were part of the Child and Family Study, a prospective multi-site study seeking to identify novel clinical predictors of NOWS. 217 mother-infant dyads with prenatal opioid exposure were recruited from prenatal clinics and postnatally at Women and Infant\u0026rsquo;s Hospital of Rhode Island and University of Utah Hospital between 2019 and 2025. Mothers were approached for consent if prenatal opioid use was identified during pregnancy or at delivery via maternal medical record, a positive maternal urine toxicology during pregnancy or at hospital admission, and/or a positive infant umbilical or urine toxicology screen after birth. Newborns were excluded if they had congenital anomalies, genetic syndromes, metabolic disturbances, sepsis, asphyxia, seizures, respiratory failure, gestational age\u0026thinsp;\u0026lt;\u0026thinsp;33 weeks, were medically unstable for the NNNS-II exam, unable to take oral medications, or if their caregiver was unable to provide informed consent. Study procedures were approved by the Institutional Review Board of each study site and all participants provided written informed consent for their participation.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eMeasures\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eNeoNatal Neurobehavioral Scale \u0026ndash; II (NNNS-II)\u003c/h2\u003e\u003cp\u003eTrained examiners administered the NNNS-II exam to assess neonatal neurobehavior within 24\u0026ndash;48 hours after birth, prior to NOWS treatment. The NNNS-II is a revised and shortened version of the original NNNS exam\u0026mdash;a comprehensive standardized evaluation of newborn neurobehavioral performance highlighting neurobehavioral regulation, reflexes, tone and signs of stress and abstinence in the neonate [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In the NNNS-II, the original NNNS summary scales were refined and items were retained that statistically contributed to the sensitivity and specificity of the exam. The NNNS-II yields 8 summary scores: attention, handling, self-regulation, arousal, tone, non-optimal reflexes, quality of movement, and stress abstinence. The 15-minute exam was conducted in the infant\u0026rsquo;s room or in a semi-private room in the nursery.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eNOWS Treatment\u003c/h3\u003e\n\u003cp\u003eInformation about NOWS symptom assessment and pharmacological treatment was abstracted from the infant\u0026rsquo;s medical record. Initiation of pharmacological treatment for NOWS was based on hospital practices at each site. Women and Infants Hospital used the Finnegan Neonatal Abstinence Scoring Tool (FNAST) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. University of Utah Hospital used Neonatal Withdrawal Inventory (NWI) and Eat Sleep Console (ESC) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Infants were assessed every 2\u0026ndash;4 hours. The FNAST is arguably the most widely used, quantifiable NOWS assessment tool. Criteria for initiating pharmacological treatment consisted of 3 consecutive scores greater than 7 or 2 consecutive scores greater than 11. The NWI is an 8-item, empirical measure of infant withdrawal derived from the FNAST. Treatment was initiated when the infant received one or more scores of 8 or higher. The ESC tool is a newer assessment focusing on vital infant functions such as eating and sleeping. Criteria for initiating pharmacological treatment were: inability for the infant to eat the appropriate amount based on age, sleep undisturbed for a minimum of 1 hour in between care times, and/or be consoled within 10 minutes [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. To account for variability in rates of pharmacological treatment based on these different assessments, we adjusted for study site in the analysis.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eMaternal substance use and maternal and infant characteristics were examined in infants treated versus those not treated for NOWS. Means and standard deviations were used for continuous measures. Categorical variables are expressed as observed counts and percentages. Significance levels for differences between treated and not treated infants were derived from one-way Analysis of Variance (ANOVA) and chi-square tests for continuous and categorical variables, respectively. Latent profile analysis (LPA) was used to classify infants into mutually exclusive neurobehavioral groups based on the 8 NNNS-II summary scores. LPA models with different numbers of profiles were fit and the model containing the optimal number of profiles was identified. Determination of the best model fit was assessed via Bayesian information criteria (BIC) with the smallest BIC value indicating the best fit as well as higher entropy, non-significant bootstrapped likelihood ratio tests and a sufficient number of cases in each profile (\u0026gt;\u0026thinsp;5% of the sample). Missing data were handled using full information maximum likelihood. To determine if NNNS-II summary scores and NNNS-II profiles were associated with the need for pharmacological treatment, we conducted logistic regression models with treatment as the dependent variable. Adjusted logistic regression models additionally controlled for study site.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eDescriptive Statistics\u003c/h2\u003e\u003cp\u003e217 mother and newborn dyads from Utah (n\u0026thinsp;=\u0026thinsp;90) and Rhode Island (n\u0026thinsp;=\u0026thinsp;127) were enrolled. Of those, 135 had an NNNS-II exam prior to becoming symptomatic for NOWS and are included in this analysis. Symptomatic was defined as at least \u003cem\u003eone\u003c/em\u003e score of an 8 or higher on the FNAST or NWI, or any \u003cem\u003eyes\u003c/em\u003e on the ESC. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e outlines participant flow from initial contact through enrollment to inclusion in this analysis. For this analysis, participants were divided into two groups: those receiving pharmacological treatment (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;37) and those that did not (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;98). Descriptive maternal and infant characteristics, separated by treatment group, are described in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Of note, the mean number of opioids mothers used did not differ between the treatment and no treatment groups (2.2 v 2.1, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.67). Polysubstance use (e.g., marijuana, tobacco, and stimulants) was more common in the treatment group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). 65% of the infants who required treatment had DCYF involvement as compared to 36% in the no treatment group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002). Additionally, fewer infants in the treatment group (48.6% v 69.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025) were breastfed. Of the 135 participants, 74 received FNAST, 21 received NWI, 24 received ESC, and 16 infants in Utah did not receive a NOWS assessment. None of the infants lacking a NOWS assessment received pharmacological treatment.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMaternal and Infant Characteristics by Infant Pharmacological Treatment Group\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTreatment\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo treatment\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;98)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM (SD) or N (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM (SD) or N (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMaternal Characteristics\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLess than high school degree\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (19.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24 (25.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.448\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdequate prenatal care\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (75.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e79 (81.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.457\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo partner\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (54.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e42 (43.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.264\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (16.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19 (19.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.672\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eResidential Treatment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (21.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 (20.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.877\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInpatient detox during pregnancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (25.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (19.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.480\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBipolar\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (32.45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (18.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.091\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePTSD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (37.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.625\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatitis C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 (41.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29 (30.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.228\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eInfant Characteristics\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex (Male)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 (40.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e52 (53.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.194\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGestational Age (weeks)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38.6 (1.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38.1 (1.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.132\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBirth Weight (grams)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2899 (547)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3014 (546)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.236\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHead circumference at birth (cm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33.3 (2.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33.7 (1.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.291\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength at birth (inches)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e47.9 (3.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48.5 (2.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.237\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDCYF Involvement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24 (64.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35 (35.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBreastfeeding\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (48.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e68 (69.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.025\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaximum Finnegan Score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.6 (1.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.7 (1.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eNote\u003c/em\u003e. PTSD\u0026thinsp;=\u0026thinsp;post-traumatic stress disorder; DCYF\u0026thinsp;=\u0026thinsp;Department of Children, Youth, and Families\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMaternal Substance Use by Infant Pharmacological Treatment Group\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTreatment\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo treatment\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;98)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eM (SD) or N (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM (SD) or N (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOpioids\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of opioids\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.2 (1.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.1 (1.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.673\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFentanyl\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (45.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e27 (28.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.050\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBuprenorphine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (67.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e56 (58.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.328\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMethadone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (35.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e32 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.844\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeroin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (32.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e28 (29.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.713\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMorphine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (18.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e19 (19.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.909\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOxycodone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (10.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e19 (19.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.308\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny illicit opioid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24 (64.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e58 (59.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.547\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOther substances\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlcohol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (13.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e11 (11.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.714\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMarijuana\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (54.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e29 (29.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNicotine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34 (91.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e66 (67.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny stimulant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e74 (75.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny benzodiazepines\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (37.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e18 (18.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.018\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny anti-anxiety\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22 (59.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e43 (44.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.129\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny anti-depressants\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (54.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e40 (41.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.198\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAny antipsychotic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (27.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e18 (18.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.294\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eNNNS-II and NOWS Treatment\u003c/h3\u003e\n\u003cp\u003eWe fit LPA models with increasing number of profiles to determine the optimal solution. Based on our selection criteria, the 3-profile solution best fit the NNNS-II data with fit statistics shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Model entropy and average class probabilities were highest for the 3-profile solution and the 4-profile solution failed to converge. Profile 1 included 20 subjects (15%, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These infants showed the lowest attention and regulation, hypotonia, and non-optimal reflexes and were classified as hypo-aroused. Profile 2 comprised of 90 subjects (67%). These infants displayed average NNNS-II scores and were labeled as showing typical neurobehavior. Profile 3 included 25 subjects (19%). This group showed high arousal and stress along with poor quality of movement and were classified as hyper-aroused.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eModel Fit Statistics for LPA Models\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber of Profiles\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eConvergence Problems\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLowest LLH Replicated\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBIC\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eEntropy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSmallest Class Size\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLMRT\u003c/p\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eBLRT\u003c/p\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2987.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2976.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.677\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e60 (44%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.277\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2992.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.842\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20 (15%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.137\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.0128\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eNote: \u003cem\u003eBIC\u003c/em\u003e sample size-adjusted Bayesian Information Criterion, \u003cem\u003eBLRT\u003c/em\u003e bootstrapped likelihood ratio test, \u003cem\u003eLLH\u003c/em\u003e log likelihood, \u003cem\u003eLMRT\u003c/em\u003e Lo\u0026ndash;Mendell\u0026ndash;Rubin test, \u003cem\u003eLPA\u003c/em\u003e latent profile analysis. Convergence problems were noted when the majority of solutions failed to converge.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eInfants with an atypical NNNS-II profile (either hyper- or hypo-aroused) were more likely to receive pharmacological treatment for NOWS (OR\u0026thinsp;=\u0026thinsp;3.45, 95% CI 1.21\u0026ndash;9.81) compared to infants with the typical profile (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.05, Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Examining individual summary scores, we found that infants with greater non-optimal reflexes were more likely to receive pharmacological treatment for NOWS (OR\u0026thinsp;=\u0026thinsp;1.55, 95% CI 1.00-2.40) and infants with increased signs of stress and abstinence were also more likely to receive treatment (OR\u0026thinsp;=\u0026thinsp;3.11, 95% CI 1.16\u0026ndash;8.33, all \u003cem\u003ep\u0026rsquo;s\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.05). Conversely, infants with better quality of movement were less likely to receive treatment (OR\u0026thinsp;=\u0026thinsp;0.53, 95% CI 0.33\u0026ndash;0.84, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;.05).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eNNNS-II Summary Scores and Profiles by Treatment\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTreatment\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo treatment\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;98)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnadjusted OR\u003c/p\u003e\u003cp\u003e(95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAdjusted OR\u003c/p\u003e\u003cp\u003e(95% CI)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNNNS-II Summary Scores\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAttention\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.8 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.0 (1.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.89 (0.57, 1.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.84 (0.52, 1.35)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHandling\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4.7 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.7 (1.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.99 (0.79, 1.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.06 (0.83, 1.36)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSelf-Regulation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4.4 (1.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.4 (1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.98 (0.69, 1.40)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.79 (0.52, 1.21)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eArousal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5.1 (2.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.2 (1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.97 (0.78, 1.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.04 (0.82, 1.33)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5.2 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.9 (0.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.63 (0.95, 2.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.44 (0.82, 2.54)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-optimal Reflexes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4.0 (1.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.8 (1.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.21 (0.82, 1.78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.55 (1.001, 2.40)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQuality of Movement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5.8 (1.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6.2 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.60 (0.39, 0.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.53 (0.33, 0.84)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStress Abstinence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.1 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.9 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.87 (1.11, 7.39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.11 (1.16, 8.33)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNNNS-II Profiles\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHyper/Hypo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15 (40.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e30 (30.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.55 (0.71, 3.39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.45 (1.21, 9.81)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTypical\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e22 (59.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e68 (69.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eNote: Adjusted OR come from models adjusted for study site. OR\u0026thinsp;=\u0026thinsp;odds ratio, CI\u0026thinsp;=\u0026thinsp;confidence interval, NNNS-II\u0026thinsp;=\u0026thinsp;NeoNatal Neurobehavioral Scale II\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe overall goal of this study was to investigate whether neonatal neurobehavioral profiles as assessed by the NNNS-II within the first two days of life were associated with the need for pharmacological treatment in infants with prenatal opioid exposure. We found that infants could be classified into one of three distinct phenotypes, a hyper-aroused profile, a typical profile, and a hypo-aroused profile (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Atypical NNNS-II profiles, which included infants that were either hyper- or hypo-aroused, were more likely to require pharmacological treatment for NOWS symptoms. Analysis of NNNS-II summary scores showed that infants with non-optimal reflexes and increased signs of stress and abstinence were more likely to receive pharmacological treatment whereas infants with better quality of movement were less likely to receive treatment. These findings reveal the importance and potential clinical utility of neonatal neurobehavioral phenotypes when predicting the need for pharmacological treatment in infants with prenatal opioid exposure.\u003c/p\u003e\u003cp\u003eNOWS severity and clinical presentation is highly variable and impacted by factors such as polysubstance use, postnatal feeding (e.g., breastfeeding vs formula), and complex social dynamics, consistent with the differences we found between the treatment and no treatment groups [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Additionally, our study confirms previous findings that infants with more signs of stress and abstinence on the NNNS are more likely to require pharmacological treatment than those who do not [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Furthermore, recent studies using the NNNS-II have shown that the NNNS-II summary scores may be associated with NOWS severity including the infant\u0026rsquo;s length of treatment and number of pharmacological medications required [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The Finnegan scoring items have also been shown to be significantly correlated with the NNNS items indicating that the NNNS can be used to supplement existing tools for identification of infants at risk for NOWS [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. When evaluating infants at risk for NOWS, it is important to consider the whole child. The NNNS-II profiles presented in this study are a holistic characterization of the child\u0026rsquo;s neurobehavioral repertoire and may have value in shaping the approach to care for infants at risk for NOWS.\u003c/p\u003e\u003cp\u003eNeonatal neurobehavioral profiles have previously been studied in various clinical populations including infants born preterm and infants with prenatal opioid exposure to identify groups of infants with similar neurobehavioral characteristics [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Profiles provide a way of looking at the whole child with clearer clinical cutoffs as compared to summary scores alone. The two dysregulated profiles seen in this study, hyper- and hypo-aroused, have been previously identified using the NNNS in a study of both term and pre-term infants with different perinatal exposures [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In a study of infants with prenatal methadone exposure, infants were classified into four profiles. Infants in profile 4 were characterized by the highest arousal, excitability, hypertonicity, non-optimal reflexes and stress abstinence and those in profile 1 exhibited the lowest attention and highest lethargy [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Beyond these populations, similar NNNS phenotypes are evident in low-risk infants with no prenatal substance exposure or other risks for neurobehavioral deficits [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Thus, the atypical hyper- and hypo-aroused profiles are commonly observed phenotypes in neonatal populations.\u003c/p\u003e\u003cp\u003eIn children with prenatal opioid exposure, atypical NNNS profiles have been associated with a greater likelihood of receiving higher doses of treatment drugs (morphine or methadone), in addition to predicting infant behavioral and developmental outcomes [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, these studies used the original version of the NNNS exam. More recently, NNNS-II profiles have been used to compare the neurobehavior of infants with and without prenatal opioid exposure revealing that infants with prenatal exposure to opioids and other psychotropic substances have distinctive patterns of neurobehavior. Four NNNS-II profiles were identified with profile 4 most closely resembling a hyper-aroused phenotype; infants in this profile were more likely to have prenatal opioid exposure compared to those in other profiles [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The present study builds upon the prior findings and is the first to show that NNNS-II profiles are associated with the need for pharmacological treatment in infants with prenatal opioid exposure.\u003c/p\u003e\u003cp\u003eThe findings of our study in conjunction with the current literature emphasize the clinical utility of the NNNS-II exam when caring for and assessing infants at risk for NOWS. These findings should be interpreted considering the following limitations. Due to a small sample size, the two atypical NNNS-II profiles were grouped together for analysis despite their opposing neurobehavioral characteristics. Future studies with a larger sample size will allow for analysis of the hyper- and hypo-aroused infants separately and therefore could provide improved clinical guidance for these vulnerable infants. Additionally, our cohort includes three different NOWS assessments which play a direct role in infants\u0026rsquo; treatment outcomes. However, this is representative of the variability in medical approaches to evaluate and care for infants with prenatal opioid exposure across the U.S. [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. It is notable that the NNNS-II was associated with the need for pharmacological treatment in our study sample despite the difference in clinical practices across sites.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, neonatal neurobehavior is associated with the need for pharmacological treatment in infants with prenatal opioid exposure. Information about NNNS-II profiles could be used to contribute to an innovative predictive model for determining whether infants with prenatal opioid exposure will require pharmacological treatment for NOWS. Early identification of those infants at risk for more severe NOWS symptoms could enable earlier treatment, potentially reducing length of stay and associated healthcare costs. Additionally, given that studies using the original NNNS have shown predictive validity of NNNS profiles for downstream developmental outcomes and delays, if our profiles are similar, we can hypothesize that infants with atypical profiles will have similar developmental challenges. Further research is needed to understand the predictive properties of each atypical profile, along with the effect of opioid type and other measures of NOWS severity when predicting treatment outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to our study staff and the infants and their caregivers who made this study possible.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBL and EC conceptualized and designed the study and critically reviewed and revised the manuscript for important intellectual content. MD and MC contributed to manuscript conceptualization. MD and MRH performed data collection and prepared the initial draft of the manuscript. LD and MC carried out the statistical analyses. All authors critically reviewed, edited, and finalized the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eAll phases of this study were supported by the National Institute of Drug Abuse: R01DA049755\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eThe authors have no competing interests relevant to this article to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy procedures were approved by the Institutional Review Board (IRB) of each study site and all participants provided written informed consent for their participation. All methods were performed in accordance with relevant guidelines and regulations.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLogan BA, Brown MS, Hayes MJ. Neonatal Abstinence Syndrome: Treatment and Pediatric Outcomes. Clin Obstet Gynecol. 2013;56(1):186\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKraft WK, Stover MW, Davis JM. Neonatal abstinence syndrome: Pharmacologic strategies for the mother and infant. Semin Perinatol. 2016;40(3):203\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePatrick SW, Barfield WD, Poindexter BB, COMMITTEE ON FETUS AND NEWBORN, COMMITTEE ON SUBSTANCE USE AND PREVENTION, Cummings J, Hand I, et al. Neonatal Opioid Withdrawal Syndrome. Pediatrics. 2020;146(5):e2020029074.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNeonatal Abstinence Syndrome Births: Trends in the United States, 2008\u0026ndash;2019 [Internet]. Agency for Healthcare Research and Quality; 2020. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003c/span\u003e\u003cspan address=\"http://www.hcup-us.ahrq.gov/reports.jsp\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHirai AH, Ko JY, Owens PL, Stocks C, Patrick SW. Neonatal Abstinence Syndrome and Maternal Opioid-Related Diagnoses in the US, 2010\u0026ndash;2017. JAMA. 2021;325(2):146.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMascarenhas M, Wachman EM, Chandra I, Xue R, Sarathy L, Schiff DM. Advances in the Care of Infants With Prenatal Opioid Exposure and Neonatal Opioid Withdrawal Syndrome. Pediatrics. 2024;153(2):e2023062871.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGrossman MR, Berkwitt AK, Osborn RR, Xu Y, Esserman DA, Shapiro ED, et al. An Initiative to Improve the Quality of Care of Infants With Neonatal Abstinence Syndrome. Pediatrics. 2017 June 1;139(6):e20163360.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHahn PD, Graham DA, Ozonoff A, Milliren CE. Neonatal Opioid Withdrawal Syndrome Treatment Guidelines and Birth Hospital Utilization. Pediatrics. 2024 July 1;154(1):e2023063635.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMills-Huffnagle S, Nyland JE. Potential problems and solutions of opioid-based treatment in neonatal opioid withdrawal syndrome (NOWS): a scoping review protocol. BMJ Open. 2023;13(2):e067883.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eReese TJ, Wiese AD, Leech AA, Domenico HJ, McNeer EA, Davis SE, et al. Adapting a Risk Prediction Tool for Neonatal Opioid Withdrawal Syndrome. Pediatrics. 2025;155(4):e2024068673.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchiff DM, Grossman MR. Beyond the Finnegan scoring system: Novel assessment and diagnostic techniques for the opioid-exposed infant. Semin Fetal Neonatal Med. 2019;24(2):115\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eConradt E, Tronick E, Lester BM. Evidence for neurobehavioral risk phenotypes at birth. Pediatr Res. 2025;97(1):99\u0026ndash;106.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu J, Bann C, Lester B, Tronick E, Das A, Lagasse L, et al. Neonatal Neurobehavior Predicts Medical and Behavioral Outcome. Pediatrics. 2010;125(1):e90\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCzynski AJ, Davis JM, Dansereau LM, Engelhardt B, Marro P, Bogen DL, et al. Neurodevelopmental Outcomes of Neonates Randomized to Morphine or Methadone for Treatment of Neonatal Abstinence Syndrome. J Pediatr. 2020;219:146\u0026ndash;151.e1.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFlannery T, Davis JM, Czynski AJ, Dansereau LM, Oliveira EL, Camardo SA, et al. Neonatal Abstinence Syndrome Severity Index Predicts 18-Month Neurodevelopmental Outcome in Neonates Randomized to Morphine or Methadone. J Pediatr. 2020;227:101\u0026ndash;107.e1.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCoyle MG, Salisbury AL, Lester BM, Jones HE, Lin H, Graf-Rohrmeister K, et al. Neonatal neurobehavior effects following buprenorphine versus methadone exposure: Opioid-exposed neonatal neurobehavior. Addiction. 2012;107:63\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLester BM, Tronick EZ. History and description of the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Pediatrics. 2004;113(3 Pt 2):634\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaylott SE, Bruce M, Brown L, Castano AJ, Dansereau L, Lester B, et al. Neonatal Neurobehavior Predicts Neonatal Opioid Withdrawal Syndrome Severity Prior to Treatment Interventions. J Pediatr. 2025 June;281:114533.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMerhar SL, Yolton K, DeMauro SB, Beiersdorfer T, Newman JE, Lorch SA, et al. Neurobehavioral Profiles in Opioid-Exposed and Unexposed Neonates. J Pediatr. 2025 June;281:114527.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFinnegan LP, Connaughton JF, Kron RE, Emich JP. Neonatal abstinence syndrome: assessment and management. Addict Dis. 1975;2(1\u0026ndash;2):141\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZahorodny W, Rom C, Whitney W, Giddens S, Samuel M, Maichuk G, et al. The Neonatal Withdrawal Inventory: A Simplified Score of Newborn Withdrawal. J Dev Behav Pediatr. 1998;19(2):89\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoung LW, Ounpraseuth ST, Merhar SL, Hu Z, Simon AE, Bremer AA, et al. Eat, Sleep, Console Approach or Usual Care for Neonatal Opioid Withdrawal. N Engl J Med. 2023 June 22;388(25):2326\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGrisham LM, Stephen MM, Coykendall MR, Kane MF, Maurer JA, Bader MY. Eat, Sleep, Console Approach: A Family-Centered Model for the Treatment of Neonatal Abstinence Syndrome. Adv Neonatal Care. 2019;19(2):138\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWouldes TA, Lester BM. Opioid, methamphetamine, and polysubstance use: perinatal outcomes for the mother and infant. Front Pediatr. 2023;11:1305508.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChu L, McGrath JM, Qiao J, Brownell E, Recto P, Cleveland LM, et al. A Meta-Analysis of Breastfeeding Effects for Infants With Neonatal Abstinence Syndrome. Nurs Res. 2022;71(1):54\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoreland A, Newman C, Crum KI, Are F. Types of child maltreatment and child welfare involvement among opioid-using mothers involved in substance use treatment. Child Youth Serv Rev. 2021 July 1;126:106021.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVelez ML, Jansson LM, Schroeder J, Williams E. Prenatal Methadone Exposure and Neonatal Neurobehavioral Functioning. Pediatr Res. 2009;66(6):704\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChin Foo CA, Dansereau LM, Hawes K, Oliveira EL, Lester BM. Improving the Assessment of Neonatal Abstinence Syndrome (NAS). Children. 2021;8(8):685.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCamerota M, McGowan EC, Aschner J, Stroustrup A, Karagas MR, Conradt E, et al. Prenatal and perinatal factors associated with neonatal neurobehavioral profiles in the ECHO Program. Pediatr Res. 2023;94(2):762\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWouldes TA, Woodward LJ. Neurobehavior of newborn infants exposed prenatally to methadone and identification of a neurobehavioral profile linked to poorer neurodevelopmental outcomes at age 24 months. Jacobson S, editor. PLOS ONE. 2020;15(10):e0240905.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSucharew H, Khoury JC, Xu Y, Succop P, Yolton K. NICU Network Neurobehavioral Scale Profiles Predict Developmental Outcomes in a Low-Risk Sample: NNNS profiles predict developmental outcomes. Paediatr Perinat Epidemiol. 2012 July;26(4):344\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoung LW, Hu Z, Annett RD, Das A, Fuller JF, Higgins RD, et al. Site-level variation in the characteristics and care of infants with neonatal opioid withdrawal. Pediatrics. 2021;147(1).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWeller AE, Crist RC, Reiner BC, Doyle GA, Berrettini WH. Neonatal Opioid Withdrawal Syndrome (NOWS): A Transgenerational Echo of the Opioid Crisis. Cold Spring Harb Perspect Med. 2021;11(3):a039669.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8099613/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8099613/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e Examine whether neonatal neurobehavioral profiles are related to need for pharmacological treatment among infants with prenatal opioid exposure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design: \u003c/strong\u003eProspective cohort study of 217 infants with need for treatment determined using the Finnegan Neonatal Abstinence Tool (FNAST), Neonatal Withdrawal Inventory (NWI), or Eat Sleep Console (ESC). Neurobehavior was assessed with the NeoNatal Neurobehavioral Scale II (NNNS-II). Latent Profile Analysis (LPA) classified infants into neurobehavioral profiles and logistic regression assessed the association between NNNS-II profiles and need for treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003eA 3-profile LPA solution best fit the NNNS-II data comprised of typical (67%), hyper-aroused (19%) and hypo-aroused groups (15%). Infants with atypical NNNS-II profiles were more likely to receive treatment (OR=3.45, 95% CI 1.21-9.81) compared to infants with typical profiles (\u003cem\u003ep \u003c/em\u003e\u0026lt; .05,\u003cstrong\u003e \u003c/strong\u003eTable 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003eNewborn neurobehavioral profiles may aid in early identification of infants requiring pharmacological treatment for opioid withdrawal, reducing length of stay and healthcare costs.\u003c/p\u003e","manuscriptTitle":"Association between NNNS-II Profiles and Pharmacological Treatment in Infants with Prenatal Opioid Exposure","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-26 09:08:15","doi":"10.21203/rs.3.rs-8099613/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-11-25T14:33:41+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-11-24T15:36:39+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-11-18T20:03:09+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-11-18T01:09:17+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-11-14T16:00:17+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-11-14T15:31:05+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-13T17:05:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-12T20:44:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Perinatology","date":"2025-11-12T20:44:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"93b56cb5-0b70-4481-acf7-8ec44234234f","owner":[],"postedDate":"November 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":58008085,"name":"Health sciences/Health care/Paediatrics"},{"id":58008086,"name":"Health sciences/Health care/Diagnosis/Physical examination"}],"tags":[],"updatedAt":"2026-03-21T07:11:27+00:00","versionOfRecord":{"articleIdentity":"rs-8099613","link":"https://doi.org/10.1038/s41372-026-02628-7","journal":{"identity":"journal-of-perinatology","isVorOnly":false,"title":"Journal of Perinatology"},"publishedOn":"2026-03-20 04:00:00","publishedOnDateReadable":"March 20th, 2026"},"versionCreatedAt":"2025-11-26 09:08:15","video":"","vorDoi":"10.1038/s41372-026-02628-7","vorDoiUrl":"https://doi.org/10.1038/s41372-026-02628-7","workflowStages":[]},"version":"v1","identity":"rs-8099613","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8099613","identity":"rs-8099613","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}