Video Abstract

Video Abstract

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BACKGROUND:

As rates of neonatal opioid withdrawal are increasing, the need for research to evaluate new treatments is growing. Large heterogeneity exists in health outcomes reported in current literature. Our objective is to develop an evidence-informed and consensus-based core outcome set in neonatal opioid withdrawal syndrome (NOWS-COS) for use in studies and clinical practice.

METHODS:

An international multidisciplinary steering committee was established. A systematic review and a 3-round Delphi was performed with open-ended and score-based assessments of the importance of each outcome to inform clinical management of neonatal opioid withdrawal. Interviews were conducted with parents and/or caregivers on outcome importance. Finally, a consensus meeting with diverse stakeholders was held to review all data from all sources and establish a core set of outcomes with definitions.

RESULTS:

The NOWS-COS was informed by 47 published studies, 41 Delphi participants, and 6 parent interviews. There were 63 outcomes evaluated. Final core outcomes include (1) pharmacologic treatment, (2) total dose of opioid treatment, (3) duration of treatment, (4) adjuvant therapy, (5) feeding difficulties, (6) consolability, (7) time to adequate symptom control, (8) parent-infant bonding, (9) duration of time the neonate spent in the hospital, (10) breastfeeding, (11) weight gain at hospital discharge, (12) readmission to hospital for withdrawal, and (13) neurodevelopment.

CONCLUSIONS:

We developed an evidence-informed and consensus-based core outcome set. Implementation of this core outcome set will reduce heterogeneity between studies and facilitate evidence-based decision-making. Future research will disseminate all the findings and pilot test the validity of the NOWS-COS in additional countries and populations to increase generalizability and impact.

What’s Known on This Subject:

The need for clinical research to evaluate new treatment interventions for neonatal opioid withdrawal is growing as prevalence increases. Heterogeneity in outcome reporting in neonatal opioid withdrawal hinders best practice guidelines.

What This Study Adds:

Implementation of an evidence-informed and consensus-based core outcome set will improve research quality and consistency enabling comparison of studies with meaningful outcomes to improve care for neonates experiencing opioid withdrawal.

The number of reported opioid exposures during pregnancy has continued to increase over the past decade, reflecting an overall rise in opioid prescribing.1,2  At birth, the newborn’s opioid exposure is discontinued, which can perpetuate a withdrawal syndrome. Neonatal opioid withdrawal syndrome (NOWS) reflects a subset of neonatal abstinence syndrome (NAS) in which neonates develop withdrawal at birth after prolonged exposure to an addictive substance such as heroin or opioid medication during pregnancy. NAS refers to neonatal withdrawal after any addictive substance exposure but has historically been used to describe neonates withdrawing from opioids.3  Depending on geographical location and assessment tools used, the birth prevalence of NOWS reportedly ranges between 5.4 and 286 per 1000 live births in Canada alone.1,4,5  Current management of NOWS varies widely; multiple practice guidelines containing recommendations exist, and only some are based on research evidence.6,7 

Given the increasing rate of NOWS,2  the heterogeneity in scoring tools and practice guidelines,8  and the need to develop appropriate formulations and effective interventions, further research is urgently required.9  Pregnant persons and children have been historically excluded from clinical trials.10,11  The complex ethical and operational considerations for conducting research during pregnancy and the social risk factors for opioid dependency create hesitancies to participate in research, with concerns for child welfare engagement and unwanted sharing of health information.12 

Authors of a recent review highlighted that a limited number of studies included families in study design, primarily outcome selection.13  In neonatology, clinical trial populations are small, and studies are often underpowered to answer additional effectiveness questions or conduct meaningful subgroup analysis.14,15  This compounds the need and relevance for meta-analysis (or data pooling) of multiple studies’ results to answer important questions on interventions’ safety and effectiveness. However, one of the most limiting factors to meta-analysis in research on NOWS and NAS is the heterogeneity of the current selection of outcomes.13,16 

To overcome the problem of heterogeneous outcomes selection and ensure that studies can be compared internationally, a core outcome set (COS) is needed. A COS is a minimum set of outcomes that are suitable for use in quality improvement in clinical practice and are meaningful to families.17  Our objective was to develop an evidence-informed, consensus-based set of core outcomes to be measured in all studies of neonates experiencing withdrawal after in utero opioid exposure. This includes neonates exposed to either illicit opioids or prescription opioids or both, including opioid replacement therapy during pregnancy. Not included in this COS, although potentially relevant, are withdrawals after exposure to other substances (eg, antidepressants or cocaine) or iatrogenic opioid withdrawal. The core outcome set in neonatal opioid withdrawal syndrome (NOWS-COS) applies to studies of all treatments, including nonpharmacologic management and quality improvement initiatives (eg, eat, sleep, console) in the defined population.7 

This study was registered with Core Outcome Measures in Effectiveness Trials (http://www.comet-initiative.org/studies/details/808)18  and received ethics approval from the Health Research Ethics Board at the University of Manitoba. A full description of our methods is available in our protocol,19  which was prospectively published.19  The current report was drafted according to Core Outcome Set–Standards for Reporting guidelines.17  The NOWS-COS was developed by using standard guidance for developing reporting guidelines,20,21  which includes a systematic review, parent and/or caregiver interviews, Delphi process, and consensus meeting. The methods for the systematic review, parent and/or caregiver interviews, Delphi, and consensus meeting are summarized below.

The initial list of candidate outcomes for inclusion in the COS was derived from the published scientific literature and an open-ended survey of physicians (neonatology, obstetrics, pediatrics, addiction medicine), nurses, nurse practitioners, social workers, and pharmacists. These stakeholder groups were selected to represent the diversity of the care team involved in the clinical management of neonates with in utero opioid exposures. Each stakeholder group had representation on the international steering committee with members from Canada, the United States, the United Kingdom, and Europe.

Shan et al,13  performed a systematic review of all studies reporting treatment outcomes in NAS and neonatal opioid withdrawal. The search strategy (available in the protocol) was designed with an experienced research librarian. Studies were screened, and data were extracted by independent investigators in duplicate. Studies in which authors examined in utero opioid exposures and reported treatment outcomes were included. All intervention types were considered (pharmacologic, nonpharmacologic). The included nonpharmacologic studies provided an overview on the practices, barriers, and effective strategies to promote nonpharmacologic management for neonates experiencing opioid withdrawal.7 

Delphi participants were selected from corresponding authors on studies identified in the systematic review and on the basis of recommendations from the steering committee (L.E.K., S.M., L.M.J., W.M., S.S., K.A., and M.O.). Because there are no standard methods for calculating sample size for a Delphi process,22  a purposive approach was taken to ensure that multiple clinical groups were represented including neonatologists, nurses, and social workers.

The Delphi was administered by using Research Electronic Data Capture (REDCap) hosted at the University of Manitoba. Data on location, subspecialty, and years of practice were collected in the first round, and responses were kept confidential and were not linked to round 2 or 3. The first round consisted of an open-ended question: “Thinking about your clinical and research practice, please list up to 10 outcomes that you feel are important to inform NAS diagnosis and management.” All participants who completed round 1 were invited to participate in round 2.

The second round listed all outcomes identified in the systematic review and round 1 of the Delphi. Participants were provided with a list of outcomes in alphabetical order (to avoid the appearance of a hierarchy) and asked, “What is the importance of this health outcome in influencing your diagnosis and management of an infant with NAS?” In accordance with previous COS developers2325  and the Grading of Recommendations Assessment, Development and Evaluation working group,26  outcomes were scored by using a Likert scale: 1 to 3 is not important, 4 to 6 is important but not critical, and 7 to 9 is critical. Prespecified inclusion criteria comprised outcomes in which 70% or more of participants scored the item with an importance of 7 to 9 (critical) and <15% of participants scored the item as 1 to 3 (not important). Outcomes in which at least 70% of participants scored the item as not important and <15% of participants scored the item critical met the exclusion criteria.

In the third round of the Delphi, participants were presented with the mean, median, and range of importance scores for each outcome from round 2. Each Delphi round remained open for a minimum of 8 weeks with reminders sent every 2 weeks for those yet to respond. At the end of the Delphi, participants were asked if they wanted a copy of the study results, how best to reach them, and if they wished to attend the consensus meeting.

Recruitment posters were placed in the NICU that encouraged eligible families to contact the research team. Parents of children diagnosed with NAS were recruited while in the hospital and were provided the option to participate when convenient. Consenting parents completed in-person interviews with a second-year pediatrics resident (F.S.) on-site at the Health Sciences Centre, Winnipeg, Canada. Interviews were recorded and transcribed. Exclusion criteria included any neonatal withdrawals related to medications other than opioids, (eg, benzodiazepines, antidepressants), iatrogenic withdrawal resulting from therapeutic opioid used directly in the newborn, and failure to provide informed consent. Participants were provided with $20 gift cards in recognition of our appreciation for their time and expertise. All interview transcriptions underwent coding and thematic analysis by 2 independent researchers (F.S. and E.C.).

A purposive sample of steering committee members, Delphi participants, and stakeholder representatives (regulatory, industry) were invited to participate in the consensus meeting. Multiple stakeholder groups were represented including medicine, nursing, social work, regulatory sciences, journal editors, and industry. A full list of participants is available in the preconsensus meeting report and summary package (Supplemental Information). Before the meeting, participants were provided with an agenda, objectives, and methods and presented summary data from the systematic review, parent and/or caregiver interviews, and Delphi. The consensus definition for inclusion in the COS was aligned with the Delphi in that at least 70% of respondents had to vote that the item was critical and should be included in an NOWS-COS. Each outcome underwent a vote: if there was a disagreement, a 2-minute discussion occurred with time allotted to present arguments for inclusion or exclusion. A second vote then followed for the required outcomes. If consensus was not reached after the second vote, the outcome was moved into a postconsensus meeting discussion with a decision made by the steering committee.

Conference software (Zoom Video Communications) recorded the session and provided participants with the opportunity to vote using a deidentified poll to select “include,” “exclude,” or “not my expertise” on each item that did not reach consensus in the Delphi.

There were 3 changes to our protocol19  including a virtual consensus meeting, consideration of all parent-reported outcomes, and using REDCap software instead of DelphiManager.

The study flow is summarized in Fig 1. Following a broad search strategy, 2935 studies were screened, and 47 studies met inclusion criteria; 10 randomized controlled trials, 21 retrospective cohort studies, 6 prospective cohort studies, 4 quality improvement studies, 3 case series, 1 case report, 1 qualitative analysis, and 1 within-subject design. The study sizes ranged between 1 and 3458 (median 78) neonates and evaluated nonpharmacologic (55%; n = 26 of 47) and pharmacologic (45%; n = 21 of 47) interventions. Characteristics of included studies are highlighted elsewhere.13  There were 234 (107 primary and 127 secondary) outcomes identified. Length of stay in hospital was most commonly reported (63.8% of studies; n = 30 of 47) as a primary or secondary outcome. Most outcomes were in the resource use and pathophysiological manifestation core domains, and limited studies reported life impact and safety (adverse events), whereas no studies reported death as a primary outcome.13 

FIGURE 1

NOWS-COS overall methods and results.

FIGURE 1

NOWS-COS overall methods and results.

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There were 84 participants invited to participate in the Delphi by e-mail, 51 of which agreed to participate (Fig 1). A total of 41 respondents completed the first round of the Delphi (80% response rate). The first round of the Delphi (open ended) identified 42 potential outcomes important for evaluating treatment response in neonates experiencing opioid withdrawal. The most commonly reported (29% of participants; n = 12 of 41) outcomes were length of stay in hospital, weight gain or loss, and need for pharmacologic treatment. The outcomes identified in round 1 and from the systematic review were evaluated in the second Delphi round in which outcomes were scored on a 9-point Likert scale. In the second Delphi round, 51 outcomes were evaluated; 6 items met consensus in definitions, and 2 outcomes were excluded while 4 new outcomes were added. Maternal-infant bonding, neurodevelopmental outcomes, seizures, feeding difficulties, weight (gain or loss), and cognitive function (eg, learning, school performance) met consensus criteria. Brain natriuretic peptide levels in blood, urine, meconium, and active ear acupuncture sites were excluded. New outcomes identified were family involvement in care (if able to), medical complications occurring during withdrawal period (eg, necrotizing enterocolitis, surgery), survival, and weaning off all medications (not just opioids). The highest scoring outcome was seizures (median 9; mean 8.03; range 6–9). In the third round of the Delphi, 3 additional outcomes met our definition for consensus: family is involved in care if able to, survival, and need for pharmacologic treatment to manage withdrawal. No outcomes met our exclusion criteria in the third round of the Delphi (Fig 2).

FIGURE 2

Scoring for COS candidate items. BNP, brain natriuretic peptide; CM, consensus meeting (percentage who voted in); DR1, percentage of participants who reported this outcome in response to open-ended questions; DR2, percentage of participants who reported as critical in the second round of the Delphi; DR3, percentage of participants who reported as critical in the third round of the Delphi; ED, emergency department; NEC, necrotizing enterocolitis; PR, percentage of parent who reported this outcome; SR, percent of included studies in the systematic review that reported.

FIGURE 2

Scoring for COS candidate items. BNP, brain natriuretic peptide; CM, consensus meeting (percentage who voted in); DR1, percentage of participants who reported this outcome in response to open-ended questions; DR2, percentage of participants who reported as critical in the second round of the Delphi; DR3, percentage of participants who reported as critical in the third round of the Delphi; ED, emergency department; NEC, necrotizing enterocolitis; PR, percentage of parent who reported this outcome; SR, percent of included studies in the systematic review that reported.

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A total of 58 parents were screened for potential eligibility. Eleven cases of nonopioid exposure (9 antidepressants, 4 benzodiazepines) and 27 cases of neonatal iatrogenic withdrawal were excluded. Subsequently, 20 parents were approached, and 14 declined to participate. Six participants completed an interview with a pediatric resident physician (F.S.). Thematic analysis, completed in duplicate, was used to identify 18 unique outcomes related to the care of neonates experiencing opioid withdrawal. There were no disagreements between scorers (F.S. and E.C.) that could not be resolved through discussion. The most frequently (100%; n = 6 of 6) reported outcome was the duration until adequate symptom control. Example text to support this outcome theme included, “I’d like my baby, like, to stop it,” referring to chronic crying, and “How long am I expecting to see symptoms while my baby is there suffering?”

The consensus meeting took place virtually at the end of April 2019. There were 19 people who agreed to participate in the consensus meeting: 14 individuals voted (the principal investigator [L.E.K.] and research assistant [E.C.] did not vote), and 3 individuals were unable to attend. Voting participants included the steering committee (all of whom did not previously participate in the Delphi: n = 6 of 7), Delphi participants (n = 6 of 8), and representatives from key stakeholder groups (regulators and industry: n = 2 of 2). The meeting provided an overview of the study to date and a discussion of all outcomes identified by parents and/or caregivers. The committee discussed the provisional list of core outcomes, which comprised a total of 10 outcome items that achieved the consensus in the Delphi rounds and parent interviews. Objections were heard and discussed, and 4 items were removed (seizures, cognitive development, survival, and family being involved in care [if able to]) from the provisional list. The outcome of seizures was removed because the neonatologists and nurses in the meeting expressed this as an extremely rare outcome, some noting only seeing 1 case in the past 5 years. Cognitive development was excluded because it was felt that this is a long-term outcome (eg, school age) and would not be feasible to measure in every study. Survival was excluded because death in the neonatal period is likely to be a result of comorbidities, not the result of opioid withdrawal treatment. The outcome of the family being involved in care (if able to) was removed because this was deemed not to be a treatment outcome. Six outcomes were voted into the COS: consolability, readmission to hospital for withdrawal concerns after discharge, receiving any breast milk at discharge, dose of treatment provided, length of treatment, and treatment with >1 medication. Maternal-infant bonding was modified to parent-infant bonding to be inclusive of care provided by fathers and foster parents. The final NOWS-COS with suggested definitions and measurements is found in Table 1, and the full discussion on each outcome item is summarized in the Supplemental Information.

TABLE 1

COS for NOWS

OutcomeDefinition
Pharmacologic treatment required to manage neonatal withdrawal, “yes” or “no” Any oral or IV drugs given for withdrawal symptoms 
Total dose of opioid treatment received to manage neonatal withdrawal, mg Including before and after discharge if weaning at home 
Duration of treatment received, d From initiation to discontinuation, both in and out hospital 
Adjuvant therapy, “yes” or “no” More than one medication received to manage neonatal opioid withdrawal 
Difficulties feeding, “yes” or “no” Inability to feed in adequate quantities to support survival without tube or intravenous feeding intervention 
Consolability, “yes” or “no” Ability to settle in care provider’s arms 
Time to adequate symptom control, h From initiation of both drug and nondrug interventions 
Parent-infant bonding, “yes” or “no” Dyadic communication: the ability of the infant to transmit meaningful cues and the capacity of the parent (birth or foster) to understand and act on them 
Duration of time the neonate spent in the hospital as an inpatient (in all levels of care), No. calendar d From admission to discharge 
Receiving any breast milk at discharge, “yes” or “no” Breastfeeding, expressed maternal or donor milk, whether orally or by nasogastric tube 
Wt gain (from birth) at hospital discharge, g/kg per d From birth to discharge 
Readmission to hospital for withdrawal concerns, “yes” or “no” Return to hospital once discharged for symptoms related with neonatal withdrawal 
Neurodevelopment Definition and measurement appropriate for time of follow-up and the child’s age 
OutcomeDefinition
Pharmacologic treatment required to manage neonatal withdrawal, “yes” or “no” Any oral or IV drugs given for withdrawal symptoms 
Total dose of opioid treatment received to manage neonatal withdrawal, mg Including before and after discharge if weaning at home 
Duration of treatment received, d From initiation to discontinuation, both in and out hospital 
Adjuvant therapy, “yes” or “no” More than one medication received to manage neonatal opioid withdrawal 
Difficulties feeding, “yes” or “no” Inability to feed in adequate quantities to support survival without tube or intravenous feeding intervention 
Consolability, “yes” or “no” Ability to settle in care provider’s arms 
Time to adequate symptom control, h From initiation of both drug and nondrug interventions 
Parent-infant bonding, “yes” or “no” Dyadic communication: the ability of the infant to transmit meaningful cues and the capacity of the parent (birth or foster) to understand and act on them 
Duration of time the neonate spent in the hospital as an inpatient (in all levels of care), No. calendar d From admission to discharge 
Receiving any breast milk at discharge, “yes” or “no” Breastfeeding, expressed maternal or donor milk, whether orally or by nasogastric tube 
Wt gain (from birth) at hospital discharge, g/kg per d From birth to discharge 
Readmission to hospital for withdrawal concerns, “yes” or “no” Return to hospital once discharged for symptoms related with neonatal withdrawal 
Neurodevelopment Definition and measurement appropriate for time of follow-up and the child’s age 

IV, intravenous.

In this article, diverse perspectives from parents, health care providers, and researchers on important outcomes to be measured in NAS and/or NOWS are provided. Within the published literature, we identified heterogeneity in outcome selection and reporting, which contributes to challenges in evidence synthesis and the interpretation of available research. For example, commonly reported outcomes, such as length of stay in hospital, often reflect institutional discharge policies (eg, at-home weaning) or additional reasons for hospitalization (eg, foster care or social work consultation), which can extend stay. Length of stay in hospital as an outcome may have historically been chosen for ease of extraction and for its utility in evaluating cost-effectiveness within a single trial. Because this outcome was most commonly reported, useful for economic assessments, and met our COS inclusion criteria, it will be in the COS despite the limited external validity. We recommend authors consider the study context and their own site policies when interpreting this outcome. A COS does not preclude additional important study outcomes from being collected, reported, and analyzed. For example, a “withdrawal severity score” (eg, Finnegan score) did not meet the predefined consensus definitions for inclusion in the COS. Because many tools are available for scoring and new methods for allocating treatment arise (eg, eat, sleep, console), we believe these are important outcomes, and we recommend reporting severity scores as appropriate.

The development of an NOWS-COS is the first evidence-informed and consensus-based recommendation for outcome selection in NOWS. The current selection and reporting of outcomes in NOWS does not consider diverse perspectives, in particular from families. In our systematic review, we identified that historically, parents and family- relevant outcomes (life impact) were not often assessed. By conducting in-person interviews, our study team identified many similar outcomes. In addition, the interviews revealed that the most important outcome is the duration until adequate symptom control.

There are several limitations in our work. There were several protocol deviations, which the steering committee did not feel affected the quality of the study or merit of the findings. We were unable to secure funding for an in-person meeting; as such, our consensus meeting took place virtually, and we used REDCap software under an institutional license (instead of DelphiManager). We acknowledge the limitation that participants could not see their individual scores from the second round but were presented with aggregate data. More interviews were expected; however, many cases were missed because of staff shortages and research aversion among the population. In our original study protocol, we planned to include the parent-reported outcomes in the second round of the Delphi. We had to modify this study design aspect because parent recruitment was slower than expected because of limited funding to recruit across multiple centers and countries. The steering committee felt that all parent-reported outcomes should be discussed and voted on at the consensus meeting. There was also an unplanned time gap of several months between round 1 and round 2 of the Delphi, which may explain the attrition rate between the 2 Delphi rounds. Although participants and steering committee members represented Europe, the United Kingdom, Canada, and the United States, survey responses were only collected in English. This may limit the generalizability of our findings in other regions.

Limited guidance exists to support investigators when choosing what outcomes to measure in child health research. Recent work by the Core Outcomes in Neonatology27,28  and our NOWS-COS reflect the only 2 COSs for neonatal health developed to date. To improve care for neonates with opioid withdrawal, it is critical that studies are used to measure important and consistently defined outcomes.16  In our study, we present important stakeholder and family perspectives on what should be measured in all NOWS clinical research. Implementation of the NOWS-COS will improve the interpretation of future research and reduce heterogeneity across studies. In addition, an evidence-informed set of outcomes will be useful to evaluate quality improvement initiatives and inform the development of patient registries. This work is particularly timely because the implementation of eat, sleep, console methods for allocating treatment of neonatal opioid withdrawal requires consideration and evaluation of long-term outcomes.29,30 

We present the first NOWS-COS in an attempt to reduce variability in outcome reporting between studies and increase research impact. Future work should be used to evaluate the usability, generalizability, and measurement properties of the NOWS-COS.

We thank all of our Delphi participants and parents who completed our in-person interviews for their time and expertise.

Dr Kelly is the primary author responsible for the initial concept and chair of the steering committee, led protocol development and all study components, and wrote the first draft of the manuscript; Dr Shan is a steering committee member, screened studies in the systematic review, conducted the parent interviews, and has been involved in all aspects of study design; Dr MacVicar is a steering committee member, screened studies in the systematic review, and has been involved in all aspects of the study design and analysis. Ms Czaplinski was responsible for Delphi reporting and thematic analysis for the parent interviews; Drs Allegaert and Offringa, Ms Mousdale, Ms Simpson, and Dr Jansson are steering committee members and have been involved in all aspects of the study design and analysis; and all authors have reviewed and approved this version of the manuscript and approved the final manuscript as submitted.

FUNDING: The systematic review for the development of a core outcome set was funded by the Dr Paul H.T. Thorlakson Foundation Fund awarded to Dr Kelly at the University of Manitoba.

COS

core outcome set

NAS

neonatal abstinence syndrome

NOWS

neonatal opioid withdrawal syndrome

NOWS-COS

core outcome set in neonatal opioid withdrawal syndrome

REDCap

Research Electronic Data Capture

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

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