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.
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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.
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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.
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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.
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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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DOI: https://doi.org/10.1007/s10995-022-03521-3