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Evidence for neurobehavioral risk phenotypes at birth

Pediatric Research (2024)Cite this article

Abstract

Observations of newborn behavior provide clinicians and researchers with a first description of the neurobehavioral organization of the newborn that is largely independent of the postnatal environment. The Neonatal Network Neurobehavioral Scale (NNNS) was developed in 2004 to evaluate how prenatal exposure to substances such as cocaine is related to neurobehavioral outcomes. There are now 156 empirical articles published using the NNNS, which we review and summarize. Z-scores from published studies using the NNNS were compiled and aggregated supporting the replicability of three newborn neurobehavioral phenotypes: one typical and two that are predictive of later cognitive and behavioral delay; hyper- and hypo-dysregulated newborns. These phenotypes emerged from independent samples and research groups and were identified in a variety of populations, including infants with prenatal substance exposure, preterm infants, and healthy term infants. Our findings show that newborn neurobehavior can be measured in a reliable and valid manner and that certain behavioral phenotypes, identifiable at birth, can predict neurodevelopmental challenges. These findings have important clinical utility. Intervening early with infants exhibiting these risk phenotypes may prevent later neurodevelopmental delay.

Impact

  • We reviewed all empirical studies published using the Neonatal Network Neurobehavioral Scale and found evidence for two replicable stress phenotypes that predict later behavioral outcomes.

  • This study highlights the utility of the Neonatal Network Neurobehavioral Scale for early identification of newborn neurodevelopmental risk phenotypes.

  • Early identification of neurodevelopmental risk, when neuroplasticity is high, may ultimately reduce the burden of subsequent neurobehavioral problems through early intervention.

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Fig. 1: PRISMA 2020 flow diagram.
Fig. 2: Replicability of three neurobehavioral profiles across 13 studies.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Lester, B. M., Tronick, E. Z. & Brazelton, T. B. The Neonatal Intensive Care Unit Network Neurobehavioral Scale procedures. Pediatrics 113, 641–667 (2004).

    Article  PubMed  Google Scholar 

  2. Napiorkowski, B. et al. Effects of in utero substance exposure on infant neurobehavior. Pediatrics 98, 71–75 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Liu, J. et al. Neonatal neurobehavior predicts medical and behavioral outcome. Pediatrics 125, e90–e98, https://doi.org/10.1542/peds.2009-0204 (2010).

    Article  PubMed  Google Scholar 

  4. McGowan, E. C. et al. Analysis of neonatal neurobehavior and developmental outcomes among preterm infants. JAMA Netw. Open 5, e2222249, https://doi.org/10.1001/jamanetworkopen.2022.22249 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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.e1, https://doi.org/10.1016/j.jpeds.2019.12.018 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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.e1, https://doi.org/10.1016/j.jpeds.2020.08.034 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sucharew, H., Khoury, J. C., Xu, Y., Succop, P. & Yolton, K. NICU network neurobehavioral scale profiles predict developmental outcomes in a low-risk sample: NNNS profiles predict developmental outcomes. Paediatr. Perinat. Epidemiol. 26, 344–352, https://doi.org/10.1111/j.1365-3016.2012.01288.x (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wouldes T. A., Woodward L. J. Neurobehavior of newborn infants exposed prenatally to methadone and identification of a neurobehavioral profile linked to poorer neurodevelopmental outcomes at age 24 months. Jacobson S., ed. PLOS ONE. 15:e0240905 (2020). https://doi.org/10.1371/journal.pone.0240905

  9. Paquette, A. G. et al. Placental epigenetic patterning of glucocorticoid response genes is associated with infant neurodevelopment. Epigenomics 7, 767–779, https://doi.org/10.2217/epi.15.28 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Stroud, L. R. et al. Epigenetic regulation of placental NR3C1: Mechanism underlying prenatal programming of infant neurobehavior by maternal smoking? Child Dev. 87, 49–60, https://doi.org/10.1111/cdev.12482 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Conradt, E., Lester, B. M., Appleton, A. A., Armstrong, D. A. & Marsit, C. J. The roles of DNA methylation of NR3C1 and 11β-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics 8, 1321–1329, https://doi.org/10.4161/epi.26634 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bromer, C., Marsit, C. J., Armstrong, D. A., Padbury, J. F. & Lester, B. Genetic and epigenetic variation of the Glucocorticoid Receptor (NR3C1) in Placenta and infant neurobehavior. Dev. Psychobiol. 55, 673–683, https://doi.org/10.1002/dev.21061 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Lester, B. M. et al. Neurobehavior related to epigenetic differences in preterm infants. Epigenomics 7, 1123–1136, https://doi.org/10.2217/epi.15.63 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Paquette, A. G. et al. Placental FKBP5 genetic and epigenetic variation is associated with infant neurobehavioral outcomes in the RICHS cohort. PLoS ONE 9, e104913, https://doi.org/10.1371/journal.pone.0104913 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Marsit, C. J., Maccani, M. A., Padbury, J. F. & Lester, B. M. Placental 11-Beta Hydroxysteroid Dehydrogenase methylation is associated with newborn growth and a measure of neurobehavioral outcome. PLoS ONE 7, e33794, https://doi.org/10.1371/journal.pone.0033794 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Green, B. B. et al. Expression of imprinted genes in placenta is associated with infant neurobehavioral development. Epigenetics 10, 834–841, https://doi.org/10.1080/15592294.2015.1073880 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Marsit, C. J. et al. Placenta-imprinted gene expression association of infant neurobehavior. J. Pediatr. 160, 854–860.e2, https://doi.org/10.1016/j.jpeds.2011.10.028 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Paquette, A. G. et al. Regions of variable DNA methylation in human placenta associated with newborn neurobehavior. Epigenetics 11, 603–613, https://doi.org/10.1080/15592294.2016.1195534 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Everson, T. M. et al. Epigenome-wide analysis identifies genes and pathways linked to neurobehavioral variation in preterm infants. Sci. Rep. 9, 6322, https://doi.org/10.1038/s41598-019-42654-4 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Conradt, E. et al. Prenatal substance exposure. Neurobiol. Organ. One Mon. J. Pediatr. 163, 989–994.e1, https://doi.org/10.1016/j.jpeds.2013.04.033 (2013).

    Article  CAS  Google Scholar 

  21. Eeles, A. L. et al. Continuum of neurobehaviour and its associations with brain MRI in infants born preterm. BMJ Paediatr. Open 1, e000136, https://doi.org/10.1136/bmjpo-2017-000136 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kelly, C. E. et al. Brain structure and neurological and behavioural functioning in infants born preterm. Dev. Med Child Neurol. 61, 820–831, https://doi.org/10.1111/dmcn.14084 (2019).

    Article  PubMed  Google Scholar 

  23. George, J. M. et al. Relationship between very early brain structure and neuromotor, neurological and neurobehavioral function in infants born <31 weeks gestational age. Early Hum. Dev. 117, 74–82, https://doi.org/10.1016/j.earlhumdev.2017.12.014 (2018).

    Article  PubMed  Google Scholar 

  24. Dorner, R. A. et al. The relationship between clinical imaging and neurobehavioral assessment in posthemorrhagic ventricular dilation of prematurity. Front Physiol. 10, 64, https://doi.org/10.3389/fphys.2019.00064 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kennedy, E. et al. Profiles of neurobehavior and their associations with brain abnormalities on MRI in infants born preterm. Early Hum. Dev. 145, 105041, https://doi.org/10.1016/j.earlhumdev.2020.105041 (2020).

    Article  PubMed  Google Scholar 

  26. Brown, N. C. et al. Neurobehavior at term and white and gray matter abnormalities in very preterm infants. J. Pediatr. 155, 32–38.e1, https://doi.org/10.1016/j.jpeds.2009.01.038 (2009).

    Article  PubMed  Google Scholar 

  27. Coleman, M. B. et al. Neonatal neurobehavioral abnormalities and MRI brain injury in encephalopathic newborns treated with hypothermia. Early Hum. Dev. 89, 733–737, https://doi.org/10.1016/j.earlhumdev.2013.05.006 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Massaro, A. N. et al. Neonatal neurobehavior after therapeutic hypothermia for hypoxic ischemic encephalopathy. Early Hum. Dev. 91, 593–599, https://doi.org/10.1016/j.earlhumdev.2015.07.008 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Smith, G. C. et al. NICU stress is associated with brain development in preterm infants. Ann. Neurol. 70, 541–549, https://doi.org/10.1002/ana.22545 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Stephens, B. E. et al. Neurobehavioral assessment predicts motor outcome in preterm infants. J. Pediatr. 156, 366–371, https://doi.org/10.1016/j.jpeds.2009.09.042 (2010).

    Article  PubMed  Google Scholar 

  31. Gluckman P. D., Hanson M. A. The developmental origins of health and disease. In: Wintour E. M., Owens J. A., eds. Early Life Origins of Health and Disease. Vol 573. Springer US;1-7. https://doi.org/10.1007/0-387-32632-4_1 (2006)

  32. Wadhwa, P. Psychoneuroendocrine processes in human pregnancy influence fetal development and health. Psychoneuroendocrinology 30, 724–743, https://doi.org/10.1016/j.psyneuen.2005.02.004 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Barker, D. Fetal programming of coronary heart disease. Trends Endocrinol. Metab. 13, 364–368, https://doi.org/10.1016/S1043-2760(02)00689-6 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Sandman, C. A. et al. Corticotrophin-releasing Hormone and Fetal Responses in Human Pregnancy. Ann. N. Y Acad. Sci. 897, 66–75, https://doi.org/10.1111/j.1749-6632.1999.tb07879.x (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Monk, C. et al. Distress during pregnancy: epigenetic regulation of placenta glucocorticoid-related genes and fetal neurobehavior. Am. J. Psychiatry 173, 705–713, https://doi.org/10.1176/appi.ajp.2015.15091171 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Barros, M. C. et al. Exposure to marijuana during pregnancy alters neurobehavior in the early neonatal period. J. Pediatr. 149, 781–787, https://doi.org/10.1016/j.jpeds.2006.08.046 (2006).

    Article  CAS  Google Scholar 

  37. Velez, M. L. et al. Prenatal buprenorphine exposure and neonatal neurobehavioral functioning. Early Hum. Dev. 117, 7–14, https://doi.org/10.1016/j.earlhumdev.2017.11.009 (2018).

    Article  PubMed  Google Scholar 

  38. Coyle, M. G. et al. Neonatal neurobehavior effects following buprenorphine versus methadone exposure. Addict. Abingdon Engl. 107, 63–73, https://doi.org/10.1111/j.1360-0443.2012.04040.x (2012).

    Article  Google Scholar 

  39. LaGasse, L. L. et al. Prenatal methamphetamine exposure and neonatal neurobehavioral outcome in the USA and New Zealand. Neurotoxicol. Teratol. 33, 166–175, https://doi.org/10.1016/j.ntt.2010.06.009 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Nguyen, R. H. N. et al. Characteristics of Individuals in the United States Who Used Opioids During Pregnancy. J Womens Health https://doi.org/10.1089/jwh.2022.0118 (2022). Published online November 9jwh.2022.0118.

  41. Barros, M. CdeM., Mitsuhiro, S. S., Chalem, E., Laranjeira, R. R. & Guinsburg, R. Depression during gestation in adolescent mothers interferes with neonatal neurobehavior. Rev. Bras. Psiquiatr 35, 353–359, https://doi.org/10.1590/1516-4446-2012-0855 (2013).

    Article  PubMed  Google Scholar 

  42. Marcus, S. et al. Depressive symptoms during pregnancy: impact on neuroendocrine and neonatal outcomes. Infant Behav. Dev. 34, 26–34, https://doi.org/10.1016/j.infbeh.2010.07.002 (2011).

    Article  PubMed  Google Scholar 

  43. Gao, M. et al. Prenatal maternal transdiagnostic, RDoC-informed predictors of newborn neurobehavior: Differences by sex. Dev. Psychopathol. 33, 1554–1565, https://doi.org/10.1017/S0954579420002266 (2021).

    Article  PubMed  Google Scholar 

  44. Ostlund, B. D. et al. Intergenerational transmission of emotion dysregulation: Part II. Developmental origins of newborn neurobehavior. Dev. Psychopathol. 31, 833–846, https://doi.org/10.1017/S0954579419000440 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ostlund, B. D. et al. Maternal mindfulness during pregnancy predicts newborn neurobehavior. Dev. Psychobiol. 63, e22131, https://doi.org/10.1002/dev.22131 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Salisbury, A. L. et al. The roles of maternal depression, serotonin reuptake inhibitor treatment, and concomitant benzodiazepine use on infant neurobehavioral functioning over the first postnatal month. Am. J. Psychiatry 173, 147–157, https://doi.org/10.1176/appi.ajp.2015.14080989 (2016).

    Article  PubMed  Google Scholar 

  47. Salisbury, A. L. et al. Newborn neurobehavioral patterns are differentially related to prenatal maternal Major Depressive Disorder and Serotonin Reuptake Inhibitor treatment. Depress Anxiety 28, 1008–1019, https://doi.org/10.1002/da.20883 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lester B. M., Camerota M., Everson T. M., Nolan, C., Marsit C. Towards a More Holistic Approach to the Study of Exposures and Child Outcomes. Epigenomics 16, 635–651.

  49. Yolton, K. et al. Impact of low-level gestational exposure to organophosphate pesticides on neurobehavior in early infancy: a prospective study. Environ. Health 12, 79, https://doi.org/10.1186/1476-069X-12-79 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Xu, Y., Khoury, J. C., Sucharew, H., Dietrich, K. & Yolton, K. Low-level gestational exposure to mercury and maternal fish consumption: Associations with neurobehavior in early infancy. Neurotoxicol. Teratol. 54, 61–67 (2016). Published online April.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tian, F. Y. et al. Selenium-associated DNA methylation modifications in placenta and neurobehavioral development of newborns: an epigenome-wide study of two U.S. birth cohorts. Environ. Int 137, 105508, https://doi.org/10.1016/j.envint.2020.105508 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tung, P. W. et al. Prenatal exposure to metal mixtures and newborn neurobehavior in the Rhode Island Child Health Study. Environ. Epidemiol. 6, e194, https://doi.org/10.1097/EE9.0000000000000194 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Tehrani, J. M. et al. Human placental microRNAs dysregulated by cadmium exposure predict neurobehavioral outcomes at birth. Pediatr Res, (2022). Published online July.

  54. McEwen, B. S. Stress, adaptation, and disease: allostasis and allostatic load. Ann. N. Y Acad. Sci. 840, 33–44, https://doi.org/10.1111/j.1749-6632.1998.tb09546.x (1998).

    Article  CAS  PubMed  Google Scholar 

  55. Shonkoff, J. P. et al. The lifelong effects of early childhood adversity and toxic stress. PEDIATRICS 129, e232–e246, https://doi.org/10.1542/peds.2011-2663 (2012).

    Article  PubMed  Google Scholar 

  56. Shonkoff, J. P., Boyce, W. T. & McEwen, B. S. Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. JAMA 301, 2252, https://doi.org/10.1001/jama.2009.754 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Gao, M. et al. Developmental foundations of physiological dynamics among mother–infant dyads: The role of newborn neurobehavior. Child Dev. 93, 1090–1105, https://doi.org/10.1111/cdev.13769 (2022).

    Article  PubMed  Google Scholar 

  58. Sheinkopf, S. J. et al. Interactions between maternal characteristics and neonatal behavior in the prediction of parenting stress and perception of infant temperament. J. Pediatr. Psychol. 31, 27–40, https://doi.org/10.1093/jpepsy/jsj026 (2006).

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Lynne Dansereau and Anna Compton for helping us to compile and review manuscripts using the NNNS. We thank the many families who have enrolled in these studies. Funding: No financial assistance was received in support of this review.

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Authors and Affiliations

  1. Duke University School of Medicine, Department of Psychiatry and Behavioral Sciences, Durham, NC, USA

    Elisabeth Conradt

  2. University of Massachusetts Chan Medical School, Departments of Psychiatry and Pediatrics, Worcester, MA, USA

    Edward Tronick

  3. Brown University Alpert Medical School; Departments of Psychiatry and Pediatrics, Providence, RI, USA

    Barry M. Lester

  4. Women and Infants Hospital of Rhode Island, Center for Children and Families, Department of Pediatrics, Providence, RI, USA

    Barry M. Lester

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Dr. Elisabeth Conradt and Dr. Barry Lester conceptualized and designed the review, drafted the initial manuscript, created the tables and figures, and critically reviewed/revised the manuscript. Dr. Edward Tronick conceptualized and designed the review and critically reviewed/revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Correspondence to Elisabeth Conradt.

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Conradt, E., Tronick, E. & Lester, B.M. Evidence for neurobehavioral risk phenotypes at birth. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03353-7

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