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The Influence of Mediators on the Relationship Between Antenatal Opioid Agonist Exposure and the Severity of Neonatal Opioid Withdrawal Syndrome

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Abstract

Objectives

(1) To evaluate the direct (un-mediated) and indirect (mediated) relationship between antenatal exposure to opioid agonist medication as treatment for opioid use disorder (MOUD) and the severity of neonatal opioid withdrawal syndrome (NOWS), and (2) to understand the degree to which mediating factors influence the direct relationship between MOUD exposure and NOWS severity.

Methods

This cross-sectional study includes data abstracted from the medical records of 1294 opioid-exposed infants (859 MOUD exposed and 435 non-MOUD exposed) born at or admitted to one of 30 US hospitals from July 1, 2016, to June 30, 2017. Regression models and mediation analyses were used to evaluate the relationship between MOUD exposure and NOWS severity (i.e., infant pharmacologic treatment and length of newborn hospital stay (LOS)) to identify potential mediators of this relationship in analyses adjusted for confounding factors.

Results

A direct (un-mediated) association was found between antenatal exposure to MOUD and both pharmacologic treatment for NOWS (aOR 2.34; 95%CI 1.74, 3.14) and an increase in LOS (1.73 days; 95%CI 0.49, 2.98). Delivery of adequate prenatal care and a reduction in polysubstance exposure were mediators of the relationship between MOUD and NOWS severity and as thus, were indirectly associated with a decrease in both pharmacologic treatment for NOWS and LOS.

Conclusions for Practice

MOUD exposure is directly associated with NOWS severity. Prenatal care and polysubstance exposure are potential mediators in this relationship. These mediating factors may be targeted to reduce the severity of NOWS while maintaining the important benefits of MOUD during pregnancy.

Significance

What is already known on this subject? The use of MOUD during pregnancy improves fetal outcomes, while antenatal exposure to MOUD increases the risk of NOWS. The severity of NOWS is influenced by MOUD type, co-exposures, adequacy of prenatal care, and the infant’s gestational age.

What this study adds? This study identifies factors that mediate the direct influence of antenatal MOUD exposure on the severity of NOWS and quantifies the degree to which this mediation influences outcomes in a large and geographically diverse population. Thus, providing clinicians with potential targets to improve care for this vulnerable population.

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Data Availability

The dataset supporting the conclusions of this article are available by request to the Corresponding Author through a data use agreement. A deidentified dataset including the majority of these data is available via the NICHD DASH portal.

Code Availability

Not applicable.

Abbreviations

ACT NOW:

Advancing Clinical Trials in Neonatal Opioid Withdrawal Syndrome

APC:

Adequate prenatal care

aOR:

Adjusted odds ratio

CI:

Confidence interval

CE:

Current experience

ECHO:

Environmental influences on Child Health Outcomes

GA:

Gestational age

HEAL:

Helping to End Addiction Long-term

IRB:

Institutional Review Board

ISPCTN:

IDeA States Pediatric Clinical Trials Network

LOS:

Length of stay

MOUD:

Medication for opioid use disorder

NICHD:

Eunice Kennedy Shriver National Institute of Child Health and Human Development

NIH:

National Institutes of Health

NOWS:

Neonatal opioid withdrawal syndrome

NRN:

Neonatal Research Network

OR:

Odds ratio

OUD:

Opioid use disorder

RUCA:

Rural–urban commuting area

SD:

Standard deviation

STROBE:

Strengthening the reporting of observational studies in epidemiology

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Acknowledgements

The NIH, the NICHD, and the National Center for Advancing Translational Sciences (NCATS) provided support for the NRN. The NIH, Office of the Director, ECHO program provided support for the ISPCTN. We are indebted to our medical and nursing colleagues from the ISPCTN and NRN who participated in this study detailed in Online Resource 8.

Funding

This manuscript is the product of work from the NICHD Neonatal Research Network and the ECHO IDeA States Pediatric Clinical Trials Network. Both networks are cooperative agreements with the NIH. Only NIH staff listed as authors have contributed to this manuscript. This research was supported through the NIH HEAL Initiative under award numbers: U10 HD36790, U10 HD53089, U10 HD27904, U24OD024957, U2COD023375, UG1 HD21364, UG1 HD27853, UG1 HD68278, UG1OD024942, UG1OD024943, UG1OD024944, UG1OD024945, UG1OD024946, UG1OD024947, UG1OD024948, UG1OD024949, UG1OD024950, UG1OD024951, UG1OD024952, UG1OD024953, UG1OD024954, UG1OD024955, UG1OD024956, UG1OD024958, UG1OD024959, UL1 TR41. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Louisville School of Medicine, 571 South Floyd Street Suite 342, Louisville, KY, 40202, USA

    Lori A. Devlin

  2. Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Zhuopei Hu & Songthip Ounpraseuth

  3. Environmental Influences on Child Health Outcomes (ECHO) Program, Office of the Director, National Institutes of Health, Rockville, MD, USA

    Alan E. Simon

  4. Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA

    Robert D. Annett

  5. University of New Mexico Health Sciences Center, Albuquerque, NM, USA

    Robert D. Annett, Janell F. Fuller & Margaret M. Crawford

  6. Social, Statistical, and Environmental Sciences Unit, RTI International, Research Triangle Park, NC, USA

    Abhik Das

  7. Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA

    Rosemary D. Higgins

  8. Florida Gulf Coast University, Fort Meyers, FL, USA

    Rosemary D. Higgins

  9. Division of Neonatology, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Stephanie L. Merhar

  10. Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA

    Stephanie L. Merhar

  11. Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA

    P. Brian Smith

  12. Department of Pediatrics, West Virginia University Medical Center, Morgantown, WV, USA

    Lesley E. Cottrell & M. Cody Smith

  13. Department of Pediatrics, Connecticut Children’s Medical Center, Hartford, CT, USA

    Adam J. Czynski

  14. Nebraska Medical Center, Omaha, NE, USA

    Sarah Newman

  15. Department of Pediatrics, ChristianaCare Health Systems, Newark, DE, USA

    David A. Paul

  16. Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, OH, USA

    Pablo J. Sánchez

  17. School of Public and Community Health Sciences, University of Montana, Missoula, MT, USA

    Erin O. Semmens

  18. Department of Pediatrics, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

    Bonny L. Whalen

  19. Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Jessica N. Snowden

  20. Department of Pediatrics, University of Vermont Larner College of Medicine, Burlington, VT, USA

    Leslie W. Young

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  1. Lori A. Devlin
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Consortia

for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and the NIH Environmental influences on Child Health Outcomes (ECHO) Program Institutional Development Awards States Pediatric Clinical Trials Network

Contributions

LAD: contributed to the design, methodology, investigation, writing and drafting of the initial manuscript and additional editing, ZH: contributed to the methodology, formal analysis, writing and drafting of the initial manuscript and additional editing, SO: contributed to the methodology, formal analysis, writing and drafting of the initial manuscript and additional editing, AES: contributed to the design, methodology, writing and drafting of the initial manuscript and additional editing, RDA: investigation, review and editing of the manuscript, AD: contributed to the design, methodology, writing and drafting of the initial manuscript and additional editing, JFF: investigation, review and editing of the manuscript, RDH: contributed to the design, methodology, writing and drafting of the initial manuscript and additional editing, SLM: contributed to the design, methodology, writing and drafting of the initial manuscript and additional editing, PBS: contributed to the design, methodology, writing and drafting of the initial manuscript and additional editing, MMC: investigation and review and editing of the manuscript, LEC: investigation and review and editing of the manuscript, AJC: investigation and review and editing of the manuscript, SN: investigation and review and editing of the manuscript, DAP: investigation and review and editing of the manuscript, PJS: investigation and review and editing of the manuscript, EOS: investigation and review and editing of the manuscript, MCS: investigation and review and editing of the manuscript, BLW: design, methodology, writing and drafting of the initial manuscript and additional editing, JNS: design, methodology, investigation, writing and drafting of the initial manuscript and additional editing, LWY: contributed to the design, methodology, investigation, writing and drafting of the initial manuscript and additional editing. All authors gave approval for the version of the manuscript that was submitted and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Lori A. Devlin.

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Conflict of interest

The authors have no conflicts of interest to disclose. While NICHD and NIH ECHO staff had input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of NICHD or the ECHO program, the National Institutes of Health, the Department of Health and Human Services, or the US Government.

Ethical Approval

A central Institutional Review Board (IRB) at the University of Arkansas for Medical Sciences approved this chart review study under a waiver of consent and parental permission.

Consent to Participate

This study was IRB approved under wavier of consent. All study data are presented as a conglomerate and no individual participant data is included in this work.

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Devlin, L.A., Hu, Z., Ounpraseuth, S. et al. The Influence of Mediators on the Relationship Between Antenatal Opioid Agonist Exposure and the Severity of Neonatal Opioid Withdrawal Syndrome. Matern Child Health J 27, 1030–1042 (2023). https://doi.org/10.1007/s10995-022-03521-3

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