Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Early developmental trajectory of children with prenatal alcohol and opioid exposure



With significant increases in opioid use/misuse and persistent high prevalence of prenatal alcohol exposure (PAE), identifying infants at risk for long-term developmental sequelae due to these exposures remains an urgent need. This study reports on developmental outcomes in young children from a prospective cohort, ENRICH-1, which recruited pregnant women and followed up maternal–infant pairs.


Subjects were assigned to four study groups based on prenatal use of medications for opioid use disorder (MOUD), PAE, MOUD+PAE, and unexposed controls (UC). Mixed effects modeling was used to evaluate changes in the Bayley Scales of Infant Development-III (BSID-III) Cognitive, Language, and Motor scores between 6 and 20 months.


There was a significant three-way interaction (MOUD-by-PAE-by-Time) with respect to the BSID-III Cognitive (p = 0.045) and Motor (p = 0.033) scales. Significant changes between the two evaluations were observed for MOUD group in Cognitive and Language scores; for PAE group in Cognitive, Language, and Motor scores, and for MOUD+PAE group in Language scores after adjusting for child sex and family socio-economic status. The developmental scores for the UC remained stable.


Observed decline in neurodevelopmental scores during the first 2 years of life emphasizes the importance of a longitudinal approach when evaluating children with prenatal polysubstance exposure.


  • BSID-III scores were stable during the first 2 years of life for unexposed children.

  • BSID-III scores declined for children with prenatal exposures to alcohol and/or opioids.

  • Standard developmental tests may not be sensitive enough during the first year of life.

  • Findings emphasize the need for repeated evaluations of children who are at high risk.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Changes in BSID-III Cognitive, Language, and Motor Scores from 6 to 20 months by study group adjusted for child sex and family SES.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to a lack of data-sharing acknowledgment of de-identified data in the consent and IRB protocol. The request for data sharing can be considered on a case-by-case basis with a formal data-sharing agreement between institutions.


  1. Haight, S. C., Ko, J. Y., Tong, V. T., Bohm, M. K. & Callaghan, W. M. Opioid use disorder documented at delivery hospitalization – United States, 1999-2014. Morb. Mortal. Wkly. Rep. 67, 845–849 (2018).

    Article  Google Scholar 

  2. Conradt, E. et al. Prenatal opioid exposure: neurodevelopmental consequences and future research priorities. Pediatrics 144, e20190128 (2019).

    Article  Google Scholar 

  3. May, P. A. et al. Prevalence of fetal alcohol spectrum disorders in 4 US communities. JAMA 319, 474–482 (2018).

    Article  Google Scholar 

  4. Denny, C. H., Acero, C. S., Terplan, M. & Kim, S. Y. Trends in alcohol use among pregnant women in the U.S., 2011-2018. Am. J. Prev. Med. 59, 768–769 (2020).

    Article  Google Scholar 

  5. Coles, C. D. et al. Gestational age and socioeconomic status as mediators for the impact of prenatal alcohol exposure on development at 6 months. Birth Defects Res. 111, 789–796 (2019).

    Article  CAS  Google Scholar 

  6. Tella, P. et al. Socioeconomic diversities and infant development at 6 to 9 months in a poverty area of São Paulo, Brazil. Trends Psychiatry Psychother. 40, 232–240 (2018).

    Article  Google Scholar 

  7. Koski, M. A. & Ingram, E. M. Child abuse and neglect: effect on Bayley scale scores. J. Abnorm. Child. Psychol. 5, 79–91 (1977).

    Article  CAS  Google Scholar 

  8. Kingston, D., Tough, S. & Whitfield, H. Prenatal and postpartum maternal psychological distress and infant development: a systematic review. Child Psychiatry Hum. Dev. 43, 683–714 (2012).

    Article  Google Scholar 

  9. Bayley, N. & Psychological Corporation. Bayley Scales of Infant and Toddler Development 3rd edn (Psychological Corporation, New York, 2006).

  10. Bode, M. M., DʼEugenio, D. B., Mettelman, B. B. & Gross, S. J. Predictive validity of the Bayley, Third Edition at 2 years for intelligence quotient at 4 years in preterm infants. J. Dev. Behav. Pediatr. 35, 570–575 (2014).

    Article  Google Scholar 

  11. Skumlien, M., Ibsen, I. O., Kesmodel, U. S. & Nygaard, E. Sex differences in early cognitive development after prenatal exposure to opioids. J. Pediatr. Psychol. 45, 475–485 (2020).

    Article  Google Scholar 

  12. Hendricks, G. et al. Prenatal alcohol exposure is associated with early motor, but not language development in a South African cohort. Acta Neuropsychiatr. 32, 1–8 (2020).

    Article  Google Scholar 

  13. Hans, S. L. & Jeremy, R. J. Postneonatal mental and motor development of infants exposed in utero to opioid drugs. Infant Ment. Health J. 22, 300–315 (2001).

    Article  Google Scholar 

  14. Levine, T. A. & Woodward, L. J. Early inhibitory control and working memory abilities of children prenatally exposed to methadone. Early Hum. Dev. 116, 68–75 (2018).

    Article  Google Scholar 

  15. Messinger, D. S. et al. The Maternal Lifestyle Study: cognitive, motor, and behavioral outcomes of cocaine-exposed and opiate-exposed infants through three years of age. Pediatrics 113, 1677–1685 (2004).

    Article  Google Scholar 

  16. Bakhireva, L. N. et al. Role of caregiver-reported outcomes in identification of children with prenatal alcohol exposure during the first year of life. Pediatr. Res. 84, 362–370 (2018).

    Article  CAS  Google Scholar 

  17. Bakhireva, L. N. et al. Association between prenatal opioid exposure, neonatal opioid withdrawal syndrome, and neurodevelopmental and behavioral outcomes at 5-8 months of age. Early Hum. Dev. 128, 69–76 (2019).

    Article  CAS  Google Scholar 

  18. Bakhireva, L. N., Lowe, J. R., Gutierrez, H. L. & Stephen, J. M. Ethanol, Neurodevelopment, Infant and Child Health (ENRICH) prospective cohort: study design considerations. Adv. Pediatr. Res. 2, e20150428 (2015).

    Google Scholar 

  19. Jacobson, S. W., Chiodo, L. M., Sokol, R. J. & Jacobson, J. L. Validity of maternal report of prenatal alcohol, cocaine, and smoking in relation to neurobehavioral outcome. Pediatrics 109, 815–825 (2002).

    Article  Google Scholar 

  20. Coles, C. D. et al. Dose and timing of prenatal alcohol exposure and maternal nutritional supplements: developmental effects on 6-month-old infants. Matern. Child Health J. 19, 2605–2614 (2015).

    Article  Google Scholar 

  21. Barratt, W. The Barratt Simplified Measure of Social Status (Indiana State University, Indiana, 2006).

  22. Bender, R. & Lange, S. Adjusting for multiple testing–when and how? J. Clin. Epidemiol. 54, 343–349 (2001).

    Article  CAS  Google Scholar 

  23. Neter, J., Kutner, M. H., Nachtsheim, C. J. & Wasserman, W. Applied Linear Statistical Models 4th edn (Irwin, Chicago, 1996).

  24. SAS Institute Inc. Sas/Stat User’s Guide, Version 15.2, ‘the Mixed Procedure’, Cary, NC.

  25. Flannery, T. et al. Neonatal Abstinence Syndrome Severity Index predicts 18-month neurodevelopmental outcome in neonates randomized to morphine or methadone. J. Pediatr. 227, 101–107 (2020).

    Article  CAS  Google Scholar 

  26. McGowan, E. C. & Vohr, B. R. Neurodevelopmental follow-up of preterm infants: what is new? Pediatr. Clin. North Am. 66, 509–523 (2019).

    Article  Google Scholar 

  27. Bayley, N. Bayley Scales of Infant and Toddler Development (PsychCorp, Pearson, 2006).

  28. Kaltenbach, K. et al. Prenatal exposure to methadone or buprenorphine: early childhood developmental outcomes. Drug Alcohol Depend. 185, 40–49 (2018).

    Article  CAS  Google Scholar 

  29. Nguyen, T. N. et al. Language trajectories of children born very preterm and full term from early to late childhood. J. Pediatr. 202, 86–91 (2018).

    Article  Google Scholar 

  30. Garrison, L., Morley, S., Chambers, C. D. & Bakhireva, L. N. Forty years of assessing neurodevelopmental and behavioral effects of prenatal alcohol exposure in infants: what have we learned? Alcohol Clin. Exp. Res. 43, 1632–1642 (2019).

    Article  Google Scholar 

  31. Subramoney, S., Eastman, E., Adnams, C., Stein, D. J. & Donald, K. A. The early developmental outcomes of prenatal alcohol exposure: a review. Front. Neurol. 9, 1108 (2018).

    Article  Google Scholar 

  32. Nygaard, E., Moe, V., Slinning, K. & Walhovd, K. B. Longitudinal cognitive development of children born to mothers with opioid and polysubstance use. Pediatr. Res. 78, 330–335 (2015).

    Article  CAS  Google Scholar 

  33. Lee, S. J., Pritchard, V. E., Austin, N. C., Henderson, J. M. T. & Woodward, L. J. Health and neurodevelopment of children born to opioid-dependent mothers at school entry. J. Dev. Behav. Pediatr. 41, 48–57 (2020).

    Article  Google Scholar 

  34. Woodward, L. J., Edgin, J. O., Thompson, D. & Inder, T. E. Object working memory deficits predicted by early brain injury and development in the preterm infant. Brain 128, 2578–2587 (2005).

    Article  Google Scholar 

  35. Lowe, J. R. et al. Early working memory as a racially and ethnically neutral measure of outcome in extremely preterm children at 18-22 months. Early Hum. Dev. 89, 1055–1061 (2013).

    Article  Google Scholar 

  36. Lowe, J. R. et al. Maternal verbal scaffolding: association with higher language skills for 20-month-old children with prenatal polysubstance exposure. Early Hum. Dev. 160, e105423 (2021).

    Article  Google Scholar 

  37. Landry, S. H., Smith, K. E., Swank, P. R., Assel, M. A. & Vellet, S. Does early responsive parenting have a special importance for children’s development or is consistency across early childhood necessary? Dev. Psychol. 37, 387–403 (2001).

    Article  CAS  Google Scholar 

  38. Early Childhood Technical Assistance Center. State and Jurisdictional Eligibility Definitions for Infants and Toddlers with Disabilities under Idea Part C, Chapel Hill, NC.

  39. Czynski, A. J. et al. Neurodevelopmental outcomes of neonates randomized to morphine or methadone for treatment of neonatal abstinence syndrome. J. Pediatr. 219, 146–151 (2020).

    Article  CAS  Google Scholar 

  40. Peterson, B. S. et al. Associations of maternal prenatal drug abuse with measures of newborn brain structure, tissue organization, and metabolite concentrations. JAMA Pediatr. 174, 831–842 (2020).

    Article  Google Scholar 

Download references


Research reported in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Number R01AA021771. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations



All authors have met the Pediatric Research authorship requirements. J.L. and L.N.B. conceptualized the research idea and analytical framework, provided the overall guidance and oversight, made substantial contributions to the interpretation of the data, and drafted the initial version of the manuscript. L.N.B. and J.M.S. contributed to the conceptualization of the study design for the ENRICH-1 cohort, funding acquisition, acquisition of the data, and provided oversight and supervision for all aspects of the primary data collection. J.L. oversaw collection of the neurobehavioral outcome data, scoring and validation of these data. M.H.R. and J.D. contributed to the research methodology, development of a data analysis plan (jointly with L.N.B. and J.L.), conducted formal data analyses, and contributed to drafting relevant sections of the manuscript. D.E.R. contributed to the data acquisition and data curation, quality control/quality assurance efforts, interpretation of data, literature review, and drafting of the manuscript. All authors provided revisions for important intellectual content and approved the final version of the manuscript.

Corresponding author

Correspondence to Ludmila N. Bakhireva.

Ethics declarations

Competing interests

The authors declare no competing interests.

Consent to participate

Written informed consent was obtained from all participants.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lowe, J.R., DiDomenico, J., Stephen, J.M. et al. Early developmental trajectory of children with prenatal alcohol and opioid exposure. Pediatr Res (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI:


Quick links