Development and Implementation of a Mobile Tool for High-Risk Pregnant Women to Deliver Effective Caregiving for Neonatal Abstinence Syndrome: Protocol for a Mixed Methods Study

Background The United States continues to experience an alarming rise in opioid use that includes women who become pregnant and related neonatal abstinence syndrome (NAS) in newborns. Most newborns experiencing NAS require nonpharmacological care, which entails, most importantly, maternal involvement with the newborn. To facilitate positive maternal-newborn interactions, mothers need to learn effective caregiving NAS strategies when they are pregnant; however, an enormous gap exists in the early education of mothers on the symptoms and progression of NAS, partly because no education, training, or other interventions exist to prepare future mothers for the challenges of caring for their newborns at risk for NAS. Objective In this paper, we describe a mixed methods, multistage study to adapt an existing mobile NAS tool for high-risk pregnant women and assess its usability, acceptability, and feasibility in a small randomized controlled trial. Methods Stage 1 will include 20 semistructured interviews with a panel of neonatology experts, NAS care providers, and mothers with experience caring for NAS-affected newborns to gather their recommendations on the management of NAS and explore their perspectives on the care of these newborns. The findings will guide the adaptation of existing mobile NAS tools for high-risk pregnant women. In stage 2, we will test the usability, acceptability, and feasibility of the adapted mobile tool via surveys with 10 pregnant women receiving opioid agonist therapy (OAT). Finally, in stage 3, we will randomize 30 high-risk pregnant women receiving OAT to either receive the adapted mobile NAS caregiving tool or usual care. We will compare these women on primary outcomes—maternal drug relapse and OAT continuation—and secondary outcomes—maternal-newborn bonding; length of newborn hospital stays; readmission rates; breastfeeding initiation and duration; and postpartum depression and anxiety at 4, 8, and 12 weeks postpartum. Results This project was funded in July 2020 and approved by the institutional review board in April 2020. Data collection for stage 1 began in December 2020, and as of January 2021, we completed 18 semistructured interviews (10 with NAS providers and 8 with perinatal women receiving OAT). Common themes from all interviews will be analyzed in spring 2021 to inform the adaptation of the NAS caregiving tool. The results from stage 1 are expected to be published in summer 2021. Stage 2 data collection will commence in fall 2021. Conclusions The findings of this study have the potential to improve NAS care and maternal-newborn outcomes and lead to commercialized product development. If effective, our new tool will be well suited to tailoring for other high-risk perinatal women with substance use disorders. Trial Registration ClinicalTrials.gov NCT04783558; https://clinicaltrials.gov/ct2/show/NCT04783558 International Registered Report Identifier (IRRID) DERR1-10.2196/27382

1 K01 DA051780-01 3 CMPC BURDULI, E allow me to pursue my long-term career goal of becoming an independent investigator with an established program of research focused on the development, implementation, and testing of interventions for substance using perinatal women and reduction of poor health outcomes for substance using perinatal women and their newborns.

PUBLIC HEALTH RELEVANCE:
Most newborns experiencing Neonatal Abstinence Syndrome (NAS) require non-pharmacologic care, which entails, most importantly, maternal involvement with her newborn. To facilitate positive maternal-newborn interactions, mothers need to learn effective caregiving NAS strategies while they are pregnant, yet, an enormous gap exists in the early education of mothers on the symptoms and progression of NAS, in part because no interventions exist to prepare future mothers for the challenges of caring for their newborns at risk for NAS. In this project, I propose to adapt an existing mobile NAS tool for high-risk pregnant women and assess its usability, acceptability, and feasibility in a small randomized controlled analog trial, and engage in career development and training activities that will enhance my expertise in the development, implementation, and testing of interventions for substance using perinatal women. Overall Impact: This career development award application is considered to be high impact due to the excellent qualifications of the candidate, a PhD psychologist with a research background in birth satisfaction and birth outcomes as well as a postdoc in substance use disorders and health disparities, the complementary expertise of an esteemed mentorship team with an established track record of collaboration and mentorship, and the clearly delineated training plan and candidate goals. The candidate has been extremely productive and articulates her commitment to the research area and her future plans clearly. Several minor concerns regarding the research plan in terms of the approach to adaptation of the existing tool and the ability to obtain data to inform a future grant proposal from the proposed study as well as potential concerns about the fact that the second mentor is located across the country slightly weaken enthusiasm for the application, but the qualifications of the candidate and the team remain extremely compelling.

Strengths
• The candidate has been extremely productive in terms of funding and publications during her postdoctoral fellowship (17 manuscripts, 2 PI grants and multiple Co-I).
• The candidate provides a strong justification for how she identified her area of interest and how her future work will build on her prior experiences.
• Despite her impressive track record, additional training in SUD interventions in pregnant women and administration of clinical trials will be helpful in her career development. Weaknesses • None noted by reviewer. • Additional exposure to the administration of randomized trials through the mentorship team would better prepare the candidate for a future grant application.

Career Development Plan/Career Goals & Objectives
• While there is excellent statistical mentorship, additional coursework may be useful (depending on the content of the clinical trials certificate).
• The second portion of qualitative training seems to occur after the qualitative portion of the study is completed.

Strengths
• The scientific justification for the proposal is sound: OUD and NAS are significant problems and involving mothers in the care of the newborn is optimal but requires education. Prior qualitative work by the candidate demonstrates that mothers do not feel they are receiving appropriate education.
• Delivering the educational intervention via a mobile-based educational intervention is innovative and potentially scalable.
• The existence of a tool for providers that can be modified for mothers increases the feasibility of the study.
• Utilizing 2 study sites for recruitment improves feasibility and increases generalizability.

Weaknesses
• Reference is made to consulting a "qualitative expert" at WSU; if this is (or is not) Dr. Barbosa-Leiker, they should be identified.
• Significant modification of the existing tool is needed, which may increase expense and requires significant time, which is appropriately reflected in the time allotted for initial development. However, if this is to be modified based on the information from the qualitative work at the end of Aim 1 and in Aim 2, the timeline may need to be adjusted.
• Given the expected duration of NAS/implementation of ESC (frequently under a week, in most cases up to a month) the rationale for additional postpartum follow up could be further justified.
• Small sample size limits the ability to perform statistical analyses in Aim 2 and Aim 3, particularly regarding clinical outcomes. Though no power calculation is performed for this reason, this should be addressed in the proposal to delineate how feasibility and acceptability data can be obtained in preparation for a future grant application. A larger sample size seems feasible based on the timeline and would likely provide better grounding for a future grant application in this area.
• Similarly, implementing strategies for dealing with missing data may be challenging based upon the small sample size.

Strengths
• The primary mentor, Dr. McPherson, is experienced in biostatistics, clinical trial methodology, technology development and addiction treatment and education development, the areas that the • Dr. Jones is a leader in the field of interventions in pregnant and postpartum women with substance use disorder and an experienced mentor.
• Dr. Barbosa-Leiker has experience in qualitative research and can serve as a professional mentor. She has a longstanding mentorship relationship with the candidate.
• The WSU team have a track record of collaboration and a commitment to methodologic expertise.
• The mentorship team is complementary in their skills and experience.

Weaknesses
• Dr. Jones is located at UNC. Though there is a plan to address the lack of physical proximity and her unique expertise is directly relevant to the proposed project and the candidate's career goals, additional plans could be put in place if this mentorship at a distance proves challenging.

Strengths
• The resources offered by WSU, the Program of Excellence in Addiction Research, access to the NIDA clinical trials network and the partnerships with the Spokane Regional Health District and the Evergreen Recovery Center will provide an outstanding environment for the candidate.
• There is a prior track record of collaboration between the partner organizations and the mentorship team.
• Candidate has been promoted to a tenure track position.

Weaknesses
• None noted by reviewer.

Strengths
• Appropriate time for recruitment for the randomized trial

Weaknesses
• Additional time may be needed for adaptation of the educational tool prior to the RCT. Though the proposed timeline is reasonable, the sample size may be too small to be informative. • CITI training will be the most targeted training with regards to topic matter.

Protections for Human Subjects
Comments on Faculty Participation (Required; not applicable for mid-and senior-career awards): • Faculty are involved through mentorship meetings Comments on Duration (Required): • Sustained throughout the award Comments on Frequency (Required): • Monthly seminars unless integrated into mentorship meetings.

Budget and Period of Support
Recommended budget modifications or possible overlap identified: • It is not clear why 30 iPads are needed if 30 people are to be randomized and half will receive usual care. Overall Impact: The proposed K01 career development and research plan has a very high likelihood to enhance the candidate's potential for a productive, independent scientific research career in the research areas of perinatal substance use disorder and NAS prevention. This project is especially timely given the perinatal opioid epidemic. The project addresses a critical gap in perinatal SUD research, prevention of NAS. Innovation and rigor are strengths in this application due to use of emerging mHealth technologies that are scalable/replicable.. The mentoring team consists of national experts in NAS, perinatal substance use disorder and biostatistics. Given the candidates life experience, prior work and professional goals, Dr. Burduli is well matched with an expert mentoring team highly capable of providing leadership and expertise needed to successfully implement the research plan. Dr. Burduli is an outstanding candidate with an ambitious research plan. Score driving factors include candidate's prior work and publication record, innovation using mHealth with RCT design, expert mentoring team and clearly defined research project and data analysis plan. I am highly confident Dr. Burduli will be successful in meeting her career and research goals; thus significantly advancing the science of perinatal substance use disorder prevention and treatment.

Strengths
• Dr. Burduli has relevant, previous training with an expert mentoring team focused on development, implementation, interventional research in both substance using perinatal women and substance exposed newborns.
• Postdoctoral fellowship experience with application and award of pilot funding work with a large scale, state-wide datasets; and service as a Co-Principal Investigator NIAAA's Native Center for Alcohol Research and Education Program and Pilot Project • Over the past 3-5 years, Dr. Burduli has had a strong record of publications and dissemination relevant to the proposed work. Weaknesses • None noted by reviewer.

Strengths
• Dr. Burduli's proposes three career goals centered on gaining research experience in the the areas of perinatal addiction/NAS, mobile health technology research methods (RCT). Each career goal is well defined, with reasonable objectives.
• Each career goal clearly matches with the expertise of the proposed mentoring/consulting team. • Given current and former collaborations among the current members of the proposed mentoring team, there is high likelihood the candidate will have a high level of engagement in both 1:1 and K01 team meetings.

Weaknesses
• The wide breadth of training goals; though all relevant to the candidate's research area of interest, are ambitious given the time. Each of the three career goals could potentially standalone.

Strengths
• The study aims address a highly significant and growing national issue, perinatal SUD and NAS • Innovation is high with use of mHealth, operationalized in the prenatal period for prevention of NAS. • Use of a mixed methods design incorporating both qualitative methods (providers and pregnant/postpartum women) and quantitative methods provides a deeper context to help guide adaptation of the health intervention.
• Data analysis plan is appropriate.

Weaknesses
• For mHealth intervention justification of exclusion of age (<18) would strengthen design. • For mHealth intervention there is need to account for recruited pregnant women who may experience a miscarriage and/or lethal fetal event.
• Eligibility of pregnant women is limited and does not specify gestational-weeks of pregnancy, parity and/or inclusion of multifetal gestation; thus justification with regard to the proposed broad inclusion criteria would strengthen inclusion criteria.
• Dr. McPherson is a national expert in her field, and has demonstrated a strong publication and dissemination record relevant to the candidate's professional goals, including leading RCT's in opioid use disorder treatment, experimental models of addiction treatment and behavioral pharmacology behavioral and pharmacotherapeutic addiction treatment. (training goals 1-3).
• Dr. Jones is a distinguished, national expert in perinatal addiction and NAS that has relevant experience to guide candidate on work with both pregnant women as well as their infants. Further, she is the executive director of the national benchmark for residential treatment for pregnant and parenting women (Horizons, training goal 1).
• Over the past 5 years, Dr. Barbosa-Leiker (consultant) has had significant publications in both qualitative and quantitative methods and is well poised to provide oversight/mentorship for training goal 1.
• For the past several years, Drs. McPherson, Barbosa-Leiker and Roll have current evidence of significant collaboration via professional and published work, focused on a vast array of addiction research, including but not limited to contingency management interventions targeting alcohol and tobacco use disorders, data analysis and interpretation of qualitative/quantitative results (training goals 1-3).
• Dr. Johnson's is a leading expert in healthcare innovation (mhealth) via creation of decision tools, received the INTM Healthcare Innovation Challenge CMMI grant, and has recent experience as PI for a NINA-funded NAS Reference and Decision Support Tool, highly relevant expertise to assist Dr. Buldoil (training goal 2). Weaknesses • It was difficult to discern the publication and dissemination record of Dr. Johnson.

Strengths
• The environment at Spokane is outstanding due to the institutional commitment to research in substance use treatment (PEAR: a program to advance behavioral and pharmacotherapeutic interventions for addiction), bioinformatics center and proven record of support to community partners offering substance use treatment.
• The presence of highly successful programs/centers, Spokane Regional Health District's Opioid Treatment Program and Evergreen Recovery Center (enthusiastic letters of support included). Weaknesses Overall Impact: This K application is from a junior investigator at Washington State University School of Nursing. She is a strong junior investigator with a productive track record and a well described program of research. The Career development plan is strong and is aligned with the development of the candidate. The institutional commitment to the candidate is excellent. The Approach has a number of moderate weaknesses. A large concern is related to the small proposed study for the approach and its unlikely to provide adequate data for a future R01-level study. The mentorship plan has some weaknesses with no career mentor and there is no plan for career mentorship which would strengthen this application.

Strengths
• This is a strong researcher who has been very productive in her career to date publishing extensively and seeking strong connections and mentorship.

Weaknesses
• None noted by reviewer.

Strengths
• Strong career development plan • Appropriate coursework is proposed aligned with research aims.

Weaknesses
• None noted by reviewer.

Strengths
• Iterative design process • Usability assessment is not included; rigorous methods are needed to ensure the usability of the tool • Given that this is a 5 year K, I would expect the trial to be more rigorous and include a longer timeframe and/ or a larger sample.
• A sample of only 30 participants who will be randomized to separate arms has the potential to result in minimal pilot data for any future work.

Strengths
• The mentors have relevant experience and expertise and have a strong plan to support the candidate Weaknesses • A mentorship team of 2 mentors is smaller than what one would expect for a Kaward • Further the mentors provide domain expertise but a career mentor is also important • Minor (one of the two mentors is located in NC).

Strengths
• There is very strong institutional commitment to this candidate • Environment provides the resources and clinical environment to support the proposed work.

Weaknesses
• None noted by reviewer.

Strengths
• The proposed activities are definitely achievable in 5 years

Weaknesses
• Timeline is very generous for the scope of work and training proposed. • Plans to re-take the CITI course Comments on Subject Matter (Required):

Protections for Human Subjects
• The subject matter in the CITI training is acceptable Comments on Faculty Participation (Required; not applicable for mid-and senior-career awards): • The faculty will be participating in the training Comments on Duration (Required): • The duration of the training is acceptable but can certainly be more robust Comments on Frequency (Required): • This appears to be a one-time training; more frequent training me be valuable.