The ACT NOW Clinical Practice Survey: Gaps in the Care of Infants With Neonatal Opioid Withdrawal Syndrome

The ISPCTN and NRN convened a cross-disciplinary team in September 2017 to address the growing neonatal opioid crisis.^22,23  This collaboration between the ISPCTN and NRN resulted in the formation of the Advancing Clinical Trials in Neonatal Opioid Withdrawal (ACT NOW) initiative, a research alliance designed to evaluate diagnostic and treatment options for neonates experiencing withdrawal from prenatal opioid exposure. The ACT NOW collaborative is implementing a multifaceted clinical research program designed to fill these gaps, building on clinical practice surveys and observational data collection to direct future clinical trials across the United States in both urban and rural sites.

The ACT NOW Clinical Practice Survey was a cross-sectional, clinical unit–level exploratory survey conducted October 2017 to November 2017. The purpose of the survey was to identify current practice in the ISPCTN and NRN sites that would potentially participate in future ACT NOW clinical trials. The survey content was adapted in part from the 2015 Bogen et al¹⁹  survey of NOWS care and is detailed in Supplemental Table 4. The ISPCTN Data Coordinating and Operations Center (DCOC) sent the survey to principal investigators of 17 ISPCTN and 15 NRN sites with instructions for the survey to be completed by the medical director of any unit caring for infants with NOWS at their associated clinical sites. The ISPCTN DCOC used Research Electronic Data Capture to build the data collection instrument.²⁴  ISPCTN investigators received a unique link to the ACT NOW Clinical Practice Survey that allowed for individual tracking of receipt and response. At the request of the NRN coordinating center, the NRN investigators received a generic link that did not allow for individual tracking of receipt and response among NRN investigators. For a complete list of participating institutions, please see the Acknowledgments.

Results are presented as a both a number and percentage of “yes” responses. The respondent indicated which protocols and/or care measures were in place in their unit for the diagnosis and management of NOWS, including screening protocols, scoring systems used to aid in clinical decision-making, and types and weaning of pharmacologic treatment. They additionally indicated which nonpharmacologic care measures were used, the location of pharmacologic care, and first- and second-line pharmacologic treatments used when pharmacologic treatment was initiated. Respondents self-identified their unit as “NICU/PICU,” “delivery unit,” or “other.” The latter 2 categories were collapsed, and practice data are hereafter displayed as “NICU” and “non-ICU.” Respondents were able to select >1 option in any category and, in some instances, had the option to provide more detail using free text. Ninety-five percent Wilson confidence intervals (CIs) were generated around estimates, and χ² and Fisher’s exact tests were used to compare the association between unit type (NICU versus non-ICU) and reporting of each standardized protocol guiding NOWS care in each domain. The statistical software R version 3.5.3 (R Foundation for Statistical Computing, Vienna, Austria) was used for computing statistics and performing tests. No adjustments were made for multiple comparisons.

Sixty-two unit respondents, representing 54 medical centers across 28 states, responded to the ACT NOW Clinical Practice Survey. Thirty-eight ISPCTN unit respondents and 24 NRN units submitted responses, representing 32 ISPCTN medical centers and 22 NRN medical centers. All ISPCTN and NRN investigators responded to the survey for at least 1 unit in their catchment area (100% response rate). Five ISPCTN sites and 2 NRN sites submitted responses from >1 unit within a single medical center. Three centers (1 in New Mexico and 2 in Rhode Island) participate in both the ISPCTN and the NRN; all 3 centers are categorized with the ISPCTN in this survey on the basis of the initial survey invitation. Respondents self-identified as NICU (n = 48) and as delivery unit or other (combined as non-ICU; n = 14), which could include mother-infant units, inpatient general pediatric wards, or other units that provide care for infants with NOWS.

Most of the participating NICU and non-ICU sites reported standard care protocols for many NOWS management domains (Table 1). NICU representatives reported protocols for 79% to 98% of domains queried; by inspection, non-ICU units appeared slightly less likely to report protocols for NOWS care in the queried domains (64%–86%). Standardized protocols for pharmacologic care and weaning were reported more frequently in the NICU setting (92% [95% CI: 80%–97%] and 94% [95% CI: 83%–98%], respectively) compared with in the non-ICU settings (64% [95% CI: 39%–84%] for both) (P < .05 for both comparisons). Tools for monitoring infant withdrawal symptoms are characterized in Table 2. Seventy-three percent (95% CI: 59%–83%) of respondents used the modified Finnegan scoring system, 4% (95% CI: 1%–14%) used the Neonatal Withdrawal Inventory (a Finnegan-related scoring system), and the remainder used either the original Finnegan or the Neonatal Abstinence Scoring System (another Finnegan-related system).^25–27 

Seventy-nine percent of both NICU and non-ICU sites reported having policies that support implementation of nonpharmacologic therapies for stabilization and treatment of infants with in utero opioid exposure (Table 1). Respondents identified all components of nonpharmacologic care used at their site. A summary of the reported nonpharmacologic care practices is presented in Table 3. Respondents from NICUs were significantly more likely to report using “cuddlers” (75% of NICUs [95% CI: 61%–85%] vs 43% of non-ICUs [95% CI: 21%–67%]; P < .05) and breastfeeding (98% [95% CI: 89%–100%] vs 71% [45% to 88%]; P < .05) as nonpharmacologic treatment of NOWS symptoms than respondents from non-ICUs. Swaddling (98% of NICUs and 86% of non-ICUs), positioning and comfort measures (88% of NICUs and 79% of non-ICUs), avoiding overstimulation (94% of NICUs and 86% of non-ICUs), and rooming-in (60% of NICUs and 64% of non-ICUs) were the most frequently reported nonpharmacologic care measures. Infant massage (21% of NICUs and 14% of non-ICUs) and high-calorie nutrition (40% of NICUs and 43% of non-ICUs) were reported less often. Seven units selected “other” and used free text to describe nonpharmacologic care, such as elemental formula if no breast milk was available, ear muffs, dark room, single room, skin-to-skin contact, environmental control, high-calorie nutrition only if significant weight loss was present, and nonpharmacologic therapies as directed by other providers (eg, physical or occupational therapy and child-life consultation).

Respondents could select multiple locations in which pharmacologic treatment of NOWS occurred in the medical center. Overall, medical centers reported that pharmacologic care for infant exposed to opioids occurred in level 3 and level 4 NICUs (83%; 95% CI: 71%–91%) more frequently than they reported pharmacologic care occurring in other locations. Specifically, 48% (95% CI: 35%–61%) of medical centers reported pharmacologic treatment in level 2 intensive care nurseries, 15% reported pharmacologic treatment while rooming-in (95% CI: 8%–27%), 13% reported pharmacologic treatment on the pediatric ward (95% CI: 6%–24%), 7% reported pharmacologic treatment in the newborn nursery (95% CI: 3%–18%), and 7% reported pharmacologic treatment in other special NOWS care locations within the hospital (95% CI: 3%–18%). Two medical centers indicated “other” as a location of pharmacologic treatment and commented that care was provided in a dedicated NOWS unit within the NICU or in a rooming-in environment unless there were other medical indications for intensive care or no bed space available.

Morphine was the most commonly reported first-line therapy (82% of all reporting medical centers [95% CI: 69%–90%]; 40 NICUs and 9 non-ICUs); however, some centers use >1 drug as first-line therapy. Methadone (22% of all reporting medical centers [95% CI: 13%–35%]; 11 NICUs and 1 non-ICU), buprenorphine (4% of all reporting medical centers [95% CI: 1%–13%]; 2 NICUs), and clonidine (2% of all reporting medical centers [95% CI: 0%–10%]; 1 NICU) were also reported. The most commonly reported second-line pharmacologic therapies were clonidine (59% of all reporting medical centers [95% CI: 46%–71%]; 28 NICUs and 4 non-ICUs) and phenobarbital (57% of all reporting medical centers [95% CI: 44%–70%]; 26 NICUs and 5 non-ICUs), and, as with first-line therapy, some centers reported using >1 drug for second-line therapy. Methadone (11% of all reporting medical centers [95% CI: 5%–22%]; 6 NICUs) and morphine (6% of all reporting medical centers [95% CI: 2%–15%]; 3 NICUs) were also reported by a small number of sites as second-line therapy. Other second-line therapies included buprenorphine (2 NICUs), chlorpromazine (1 non-ICU), and lorazepam or other benzodiazepines (1 NICU).

The opioid crisis has affected many infants across the United States, and critical gaps remain in our knowledge of the best practices for diagnosis of NOWS and care of infants with NOWS. The strength of the ACT NOW collaborative is to join the neonatal expertise of the NRN with the ISPCTN’s mission of engaging rural and underserved areas in clinical trials. This is of particular importance given the disproportionate increase of NOWS in rural compared with urban settings.²⁸  The ACT NOW Clinical Practice Survey sites reported protocols for many elements of NOWS care, including NOWS scoring (98% of NICUs and 86% of non-ICUs), pharmacologic treatment (92% of NICU and 64% of non-ICUs), and nonpharmacologic care (79% of NICUs and 79% non-ICUs). This appears to represent an increase in several domains compared with the results of the BORN survey in 2015, in which 93% of respondents had a NOWS scoring protocol and 72% had protocols for pharmacologic care.¹⁹  Similarly, we observed a higher frequency of NOWS scoring protocols compared with that in a 2014 study in the Vermont Oxford Network, in which 77% of units reported NOWS scoring standardization.¹⁷  A majority of sites in our survey used the Finnegan scoring system or a modification of it, similar to findings of previous studies.^17–20 

As the incidence of NOWS has increased so has the use of NICUs to care for these newborns, often separating the mother-infant dyad.²⁹  In this survey, pharmacologic treatment occurred most often in the intensive care setting, with the majority occurring in level 2 to level 4 NICUs, similar to that reported in other NOWS studies.^3,19,24  Buprenorphine, which has been associated with shortened length of stay in some studies, was not widely reported in this sample.⁵ 

The use of nonpharmacologic interventions (in particular, keeping the mother with her infant) has proven to ameliorate NOWS symptoms. Higher rates of nonpharmacologic care protocols were reported in this study compared with the BORN survey. We observed that 79% of units reported protocols for nonpharmacologic care, compared with 58% of units in the BORN survey.¹⁹  More than 60% of the ACT NOW Clinical Practice Survey units reported using nonpharmacologic practices such as rooming-in, breastfeeding, positioning and comforting, swaddling, and avoiding overstimulation. The apparent increase in nonpharmacologic care practices reported may be attributable to the increasing evidence of their success, with recent studies revealing the benefits of parental presence and rooming-in on postnatal opioid exposure, hospital length of stay, breastfeeding rates, discharge from the hospital with family, and/or hospital cost.^12,30  However, only 15% of centers in the ACT NOW Clinical Practice Survey reported rooming-in during pharmacologic treatment. Overall, the non-ICUs in our survey reported fewer protocols for pharmacologic care and weaning compared with NICUs. This likely reflects the finding that pharmacologic care in general occurs more often in the NICU setting and that care in this setting is often more protocolized.^3,31,32  Non-ICU responders were also less likely to report the use of certain nonpharmacologic care measures, such as cuddlers and breastfeeding, which was somewhat unexpected and may be affected by the small number of non-ICU responders included in this sample.

There are several limitations to this survey. First, because this was intended as a clinical practice assessment for a specific clinical trial platform, only ISPCTN and NRN sites were surveyed, and the instrument was not validated, which limits the generalizability of our results. In particular, the oversampling of NICUs at academic medical centers may contribute to a higher proportion of sites with protocolized care and management in the ICU setting. There may be additional units at the participating institutions that provide care for infants with NOWS but did not respond to this survey. In addition, the brevity of the survey offered little opportunity for details regarding the implementation of protocols to guide NOWS care at the participating sites. Variability in respondents’ perceptions and reporting of NOWS care in a particular unit may have influenced the results of the survey. In addition, respondents’ reports may not account for practitioner variability within a given hospital or site. A follow-up study, ACT NOW Current Experience, is being used to obtain infant-level data on individual- and site-level variations in NOWS care within the ISPCTN and NRN collaborative to address several of these limitations.

The care of infants exposed to opioids is developing in response to the opioid crisis. These broad changes reflect a response by medical care providers to an evolving children’s health problem. Observed variations in care between NICUs and non-ICUs reveal opportunities for targeted interventions in training and standardized care plans in non-ICU sites, given the benefits associated with standardization. However, many gaps remain in our understanding of which elements of standardized care may be most beneficial, of which variations might be beneficial for certain infants, and of the long-term effects of pharmacologic and nonpharmacologic treatment options for NOWS symptoms. This survey reveals the importance of multisite clinical studies, particularly those that engage participants in the highest-risk areas, to generate data that may be generalizable to a wide range of practices. Future ACT NOW studies can be used to assess the prevalence of NOWS in different regions of the country, describe individual- and site-level variations in care for infants with NOWS, and help develop clinical trials that impact the policies and practices that guide NOWS diagnosis and treatment in the United States.

The following investigators, in addition to those listed as authors, participated in this study: ISPCTN Steering Committee Chair: Jill Joseph, MD (University of California, Davis Health); NRN Steering Committee Chair: Richard A. Polin, MD (Columbia University); Alaska Native Tribal Health Consortium, Alaska Native Medical Center, Alaska Regional Hospital, Fairbanks Memorial Hospital, and The Children’s Hospital at Providence: Lily Lou, MD, Laura Brunner, MD, Dianne Gillis, MD, and Mary Herrick, MD; Alpert Medical School of Brown University and Women and Infants Hospital of Rhode Island: Adam Czynski, MD, Abbot R. Laptook, MD, Martin Keszler, MD, Angelita M. Hensman, PhD, MS, RNC-NIC, Kristin M. Basso, MS, BSN, Andrea M. Knolls, Suzy Ventura, and Elisa Vieira, RN, BSN; Arkansas Children’s Research Institute, University of Arkansas for Medical Sciences, and University of Arkansas: Jennifer Andrews, MD, and William Greenfield, MD; Case Western Reserve University, Rainbow Babies and Children’s Hospital: Michele C. Walsh, MD, MS, Anna Marie Hibbs, MD, and Nancy S. Newman, BA, RN; Cincinnati Children’s Hospital Medical Center, University Hospital, and Good Samaritan Hospital: Brenda B. Poindexter, MD, MS, Kurt Schibler, MD, Kate Bridges, MD, Barbara Alexander, RN, Cathy Grisby, BSN, CCRC, Jody Hessling, RN, Estelle E. Fischer, MHSA, MBA, Lenora D. Jackson, CRC, Kristin Kirker, CRC, and Greg Muthig, BS; Dartmouth College, Dartmouth-Hitchcock Medical Center, and Children’s Hospital at Dartmouth-Hitchcock Medical Center: Alison Holmes, MD; Duke University School of Medicine, University Hospital, University of North Carolina at Chapel Hill, Duke Regional Hospital, and WakeMed Health and Hospitals: Wayne Price, MD, Ronald N. Goldberg, MD, C. Michael Cotten, MD, MHS, Kimberley A. Fisher, PhD, FNP-BC, IBCLC, Joanne Finkle, RN, JD, Matthew M. Laughon, MD, MPH, Carl L. Bose, MD, Janice Bernhardt, MS, RN, Gennie Bose, RN, and Stephen D. Kicklighter, MD; Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown: David P. Carlton, MD, Yvonne Loggins, RN, BSN, and Diane Bottcher, RN, MN; NICHD: Andrew Bremer, MD, and Stephanie Wilson Archer, MA; Louisiana State University and Tulane Lakeside Hospital for Women and Children: Jay P. Goldsmith, MD; Nemours/Alfred I. duPont Hospital for Children and Christiana Care Health System: David Paul, MD; McGovern Medical School at The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District: Jon E. Tyson, MD, MPH, Amir M. Khan, MD, Barbara J. Stoll, MD, Emily K. Stephens, RN, BSN, Janice John, CPNP, Daniel Sperry, RN, and Patti L. Pierce Tate, RCP; Nationwide Children’s Hospital, Research Institute at Nationwide Children’s Hospital, The Ohio State University Wexner Medical Center, The Ohio State College of Medicine, and Center for Perinatal Research: Erin Keels, DNP, APRN, NNP-BC, Pablo J. Sánchez, MD, Leif D. Nelin, MD, Sudarshan R. Jadcherla, MD, Patricia Luzader, RN, Julie Gutentag, RN, Margaret Sullivan, BA, Jennifer L. Grothouse, RN, Melanie Stein, BBA, RRT, Erna Clark, BA, and Rox Ann Sullivan, BSN; Rhode Island Hospital and Kent Hospital: Nicholas G. Guerina, MD, PhD; RTI International: Dennis Wallace, PhD, Jamie E. Newman, PhD, MPH, Jeanette O’Donnell Auman, BS, Marie G. Gantz, PhD, Carolyn M. Petrie Huitema, MS, CCRP, and Kristin M. Zaterka-Baxter, RN, BSN, CCRP; Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children’s Hospital: Krisa P. Van Meurs, MD, Valerie Y. Chock, MD, MS Epi, M. Bethany Ball, BS, CCRC, and Melinda S. Proud, RCP; University of Alabama at Birmingham Health System and Children’s Hospital of Alabama: Waldemar A. Carlo, MD, Namasivayam Ambalavanan, MD, and Shirley S. Cosby, RN, BSN; University of Hawaii at Manoa and the Kapiolani Medical Center for Women and Children: Charles Neal, MD, PhD, and Men-Jean Lee, MD; University of Iowa Stead Family Children’s Hospital: Jonathan Klein, MD, Edward F. Bell, MD, Tarah T. Colaizy, MD, MPH, Karen J. Johnson, RN, BSN, Jacky R. Walker, RN, and Kelly E. Wood, MD; University of Kansas Medical Center, the University of Kansas Health System, and Children’s Mercy Kansas City: Kourtney Bettinger, MD, Teresa Kilkenny, DNP, PNP-PC, Krishna Dummula, MD, and Danielle Reed, MD; University of Louisville, Norton Hospital Newborn Nursery, Norton Children’s Hospital, and University of Louisville Hospital: Sara Watson, MD, MS, Janice Sullivan, MD, and Jackie Perry Boyd, RN, BSN; University of New Mexico Health Sciences Center: Kristi L. Watterberg, MD, Janell F. Fuller, MD, and Jean R. Lowe, PhD; University of Mississippi Medical Center: Mobolaji Famuyide, MD, and Lauren Tucker, MD; University of Montana, Community Medical Center, Montana Children’s Medical Center, St Vincent Healthcare, and Billings Clinic: Jeff Cooper, MD, Alison Rentz, MD, Mark Kaneta, MD, and Bonnie E. Stephens, MD; University of Nebraska Medical Center: Ann Anderson Berry, MD; University of Oklahoma Health Sciences Center, Comanche County Memorial Hospital, and University of Oklahoma Children’s Hospital: Abhishek Makkar, MD, and Kimberly D. Ernst, MD, MSMI, FAAP; University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, Children’s Hospital of Philadelphia, and Virtua Voorhees Hospital: Karen Puopolo, MD, Michael Posencheg, MD, Elizabeth Fong-deLeon MD, Eric C. Eichenwald, MD, Sara B. DeMauro, MD, MSCE, Soraya Abbasi, MD, Toni Mancini, RN, BSN, CCRC, and Dara M. Cucinotta, RN; University of Rochester Medical Center, Golisano Children’s Hospital, University of Buffalo, Women’s and Children’s Hospital of Buffalo, and State University of New York at Buffalo: Praveen Chandrasekharan, MD, Ann Marie Scorsone, MS, Carl T. D’Angio, MD, Ronnie Guillet, MD, PhD, Anne Marie Reynolds, MD, MPH, Michael G. Sacilowski, BS, Cassandra A. Horihan, MS, and Ashley Williams, MSEd; University of South Carolina at Columbia, Spartanburg Medical Center, East Cooper Medical Center, Medical University Of South Carolina, McLeod Regional Medical Center, and Palmetto Health Richland: Laura Basile, MD, MSPH, Douglas Moeckel, MD, Julie Ross, MD, K. Lee, MD, and Brian Wood, MD; University of Texas Southwestern Medical Center at Dallas, Parkland Health and Hospital System, and Children’s Medical Center Dallas: Myra H. Wyckoff, MD, Luc P. Brion, MD, Diana M. Vasil, RNC, NIC, LiJun Chen, PhD, RN, Alicia Guzman, and Lizette E. Lee, RN; University of Utah Medical Center, Intermountain Medical Center, McKay-Dee Hospital, Primary Children’s Medical Center, and Utah Valley Hospital: Erick Gerday, MD, Camille Fung, MD, Bradley A. Yoder, MD, Mark Sheffield, MD, Manndi C. Loertscher, BS, CCRP, and Carrie A. Rau, RN, BSN, CCRC; University of Vermont and State Agricultural College and the University of Vermont Children’s Hospital: Charles Mercier; and West Virginia University.

The National Institutes of Health, the NICHD, and the National Center for Advancing Translational Sciences provided support for the NRN, and the National Institutes of Health, Office of the Director, Environmental Influences on Child Health Outcomes (ECHO) Program provided support for the ISPCTN. Although NICHD and ECHO staff had input in the study design, conduct, analysis, and article drafting, the comments and views of the authors do not necessarily represent the views of the NICHD or the ECHO program, the National Institutes of Health, the US Department of Health and Human Services, or the US Government. Data were collected at participating sites of the NICHD NRN, and participating sites of the ECHO ISPCTN were transmitted to the University of Arkansas for Medical Sciences, the DCOC for this study. Dr Jeannette Lee and Dr Snowden (DCOC Principal Investigators) had full access to the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. We are indebted to our medical and nursing colleagues who agreed to take part in this study.