Skip to main content

Thank you for visiting nature.com. 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.

NICU-based stress response and preterm infant neurobehavior: exploring the critical windows for exposure

Pediatric Research (2022)Cite this article

Abstract

Background

Exposure to maternal stress in utero negatively impacts cognitive and behavioral outcomes of children born at term. The neonatal intensive care unit (NICU) can be stressful for preterm infants during a developmental period corresponding to the third trimester of gestation. It is unknown whether stress in the NICU contributes to adverse neurodevelopment among NICU graduates. The aim was to examine the association between salivary cortisol and early neurodevelopment in preterm infants.

Methods

We examined the association between cortisol levels during the NICU hospitalization and subsequent performance on the NICU Network Neurobehavioral Scales (NNNS), estimating time-specific associations and considering sex differences.

Results

Eight hundred and forty salivary cortisol levels were measured from 139 infants. Average cortisol levels were inversely associated with NNNS Regulation scores for both male and female infants (β = −0.19; 95% CI: −0.44, −0.02). Critical developmental windows based on postmenstrual age were identified, with cortisol measured <30 weeks PMA positively associated with Habituation and Lethargy scores (β = 0.63–1.04). Critical developmental windows based on chronological age were identified, with cortisol measured in the first week of life inversely associated with Attention score (β = −1.01 for females; −0.93 for males).

Conclusions

Stress in the NICU at specific developmental time points may impact early preterm infant neurodevelopment.

Impact

  • Stress in the neonatal intensive care unit can impact the neurodevelopmental trajectory of premature infants.

  • The impact of stress is different at different points in development.

  • The impact of stress is sexually dimorphic.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Fig. 1: Salivary cortisol concentration (nmol/l) by the timing of specimen collection.
Fig. 2: The results of rDLM examining associations between salivary cortisol and NNNS Habituation and Lethargy scores.
Fig. 3: The results of rDLM examining associations between salivary cortisol and the NNNS Attention and Regulation scores.
Fig. 4: The results of rDLM examining the association between salivary cortisol level and Handling subscale score by PMA and CA, respectively.

References

  1. Larroque, B. et al. Survival of very preterm infants: EPIPAGE, a population based cohort study. Arch. Dis. Child. Fetal Neonatal Ed. 89, 139–144 (2004).

    Google Scholar 

  2. Helenius, K. et al. Survival in very preterm infants: an international comparison of 10 national neonatal networks. Pediatrics 140, e20171264 (2017).

  3. Younge, N. et al. Survival and neurodevelopmental outcomes among periviable infants. N. Engl. J. Med. 376, 617–628 (2017).

    PubMed  PubMed Central  Google Scholar 

  4. Hintz, S. R. et al. Early-childhood neurodevelopmental outcomes are not improving for infants born at <25 weeks’ gestational age. Pediatrics 127, 62–70 (2011).

    PubMed  PubMed Central  Google Scholar 

  5. Delobel-Ayoub, M. et al. Behavioral outcome at 3 years of age in very preterm infants: the EPIPAGE study. Pediatrics 117, 1996–2005 (2006).

    PubMed  Google Scholar 

  6. Cooke, R. W. I. & Foulder-Hughes, L. Growth impairment in the very preterm and cognitive and motor performance at 7 years. Arch. Dis. Child. 88, 482–487 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Marret, S. et al. Brain injury in very preterm children and neurosensory and cognitive disabilities during childhood: the EPIPAGE cohort study. PLoS ONE 8, e62683 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Barfield, W. D. Public health implications of very preterm birth. Clin. Perinatol. 45, 565–577 (2018).

    PubMed  PubMed Central  Google Scholar 

  9. Colvin, M., McGuire, W. & Fowlie, P. W. Neurodevelopmental outcomes after preterm birth. BMJ 329, 1390–1393 (2004).

    PubMed  PubMed Central  Google Scholar 

  10. Trasande, L. L. & Liu, T. Reducing the staggering costs of environmental disease in children, estimated at $76.6 billion in 2008. Health Aff. 30, 863–870 (2011).

    Google Scholar 

  11. Cioni, G., Inguaggiato, E. & Sgandurra, G. Early intervention in neurodevelopmental disorders: underlying neural mechanisms. Dev. Med. Child Neurol. 58, 61–66 (2016).

    PubMed  Google Scholar 

  12. Adams-Chapman, I. et al. Neurodevelopmental impairment among extremely preterm infants in the neonatal research network. Pediatrics 141, e20173091 (2018).

  13. Casavant, S. G., Cong, X., Moore, J. & Starkweather, A. Associations between preterm infant stress, epigenetic alteration, telomere length and neurodevelopmental outcomes: a systematic review. Early Hum. Dev. 131, 63–74 (2019).

    CAS  PubMed  Google Scholar 

  14. Hortensius, L. M., Van Elburg, R. M., Nijboer, C. H., Benders, M. J. & De Theije, C. G. Postnatal nutrition to improve brain development in the preterm infant: a systematic review from bench to bedside. Front. Physiol. https://doi.org/10.3389/fphys.2019.00961 (2019).

  15. Williams, M. D. & Lascelles, B. D. X. Early neonatal pain—a review of clinical and experimental implications on painful conditions later in life. Front. Pediatr. 8, 30 (2020).

    PubMed  PubMed Central  Google Scholar 

  16. Santos, J., Pearce, S. E. & Stroustrup, A. Impact of hospital-based environmental exposures on neurodevelopmental outcomes of preterm infants. Curr. Opin. Pediatr. 27, 254–260 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Jung, C. et al. Plasma, salivary and urinary cortisol levels following physiological and stress doses of hydrocortisone in normal volunteers. BMC Endocr. Disord. 14, 1–10 (2014).

    Google Scholar 

  18. Pourkaviani, S. et al. Clinical validation of the neonatal infant stressor scale with preterm infant salivary cortisol. Pediatr. Res. 87, 1237–1243 (2020).

    PubMed  Google Scholar 

  19. Anesiadou, S. et al. Salivary cortisol and alpha-amylase daily profiles and stress responses to an academic performance test and a moral cognition task in children with neurodevelopmental disorders. Stress Health 37, 45–59 (2020).

    PubMed  Google Scholar 

  20. Poole, K. L. & Schmidt, L. A. Frontal brain delta‐beta correlation, salivary cortisol, and social anxiety in children. J. Child Psychol. Psychiatry 60, 646–654 (2019).

    PubMed  Google Scholar 

  21. Herzberg, M. P., Hunt, R. H., Thomas, K. M. & Gunnar, M. R. Differential brain activity as a function of social evaluative stress in early adolescence: brain function and salivary cortisol. Dev. Psychopathol. 32, 1926–1936 (2020).

    PubMed  PubMed Central  Google Scholar 

  22. Stroud, L. R., Salovey, P. & Epel, E. S. Sex differences in stress responses: social rejection versus achievement stress. Biol. Psychiatry 52, 318–327 (2002).

    PubMed  Google Scholar 

  23. Andiarena, A. et al. Evening salivary cortisol and alpha-amylase at 14 months and neurodevelopment at 4 years: sex differences. Horm. Behav. 94, 135–144 (2017).

    CAS  PubMed  Google Scholar 

  24. Bendiksen, B. et al. The associations between pre- and postnatal maternal symptoms of distress and preschooler’s symptoms of ADHD, oppositional defiant disorder, conduct disorder, and anxiety. J. Atten. Disord. 24, 1057–1069 (2020).

    PubMed  Google Scholar 

  25. Edwards, R. C. & Hans, S. L. Prenatal depressive symptoms and toddler behavior problems: the role of maternal sensitivity and child sex. Child Psychiatry Hum. Dev. 47, 696–707 (2016).

    PubMed  Google Scholar 

  26. Plamondon, A. et al. Spatial working memory and attention skills are predicted by maternal stress during pregnancy. Early Hum. Dev. 91, 23–29 (2015).

    PubMed  Google Scholar 

  27. Simcock, G. et al. Prenatal maternal stress shapes children’s theory of mind: the 2011 Queensland Flood Study. J. Dev. Orig. Health Dis. 8, 483–492 (2017).

    CAS  PubMed  Google Scholar 

  28. Simcock, G. et al. Infant neurodevelopment is affected by prenatal maternal stress: the 2011 Queensland Flood Study. Infancy 22, 282–302 (2017).

    PubMed  Google Scholar 

  29. Zhu, P. et al. Sex-specific and time-dependent effects of prenatal stress on the early behavioral symptoms of ADHD: a longitudinal study in China. Eur. Child Adolesc. Psychiatry 24, 1139–1147 (2015).

    PubMed  Google Scholar 

  30. Quesada, A. A., Tristao, R. M., Pratesi, R. & Wolf, O. T. Hyper-responsiveness to acute stress, emotional problems and poorer memory in former preterm children. Stress 17, 389–399 (2014).

    PubMed  Google Scholar 

  31. Konkel, L. The brain before birth: using fMRI to explore the secrets of fetal neurodevelopment. Environ. Health Perspect. 126, 112001 (2018).

    PubMed  PubMed Central  Google Scholar 

  32. Horton, M. K. et al. Dentine biomarkers of prenatal and early childhood exposure to manganese, zinc and lead and childhood behavior. Environ. Int. 121, 148–158 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Chiu, Y.-H. M. et al. Prenatal particulate air pollution and neurodevelopment in urban children: examining sensitive windows and sex-specific associations. Environ. Int. 87, 56–65 (2016).

    CAS  PubMed  Google Scholar 

  34. Henn, B. C. et al. Associations of early childhood manganese and lead coexposure with neurodevelopment. Environ. Health Perspect. 120, 126–131 (2012).

    CAS  Google Scholar 

  35. Stroustrup, A. et al. Cohort profile: The neonatal intensive care unit hospital exposures and long-term health (NICU-HEALTH) cohort, a prospective preterm birth cohort in New York City. BMJ Open 9, e032758 (2019).

    PubMed  PubMed Central  Google Scholar 

  36. Mathur, A. Understanding moderate prematurity. Arch. Dis. Child. Fetal Neonatal Ed. 100, F474–F475 (2015).

  37. Natarajan, G. & Shankaran, S. Short-and long-term outcomes of moderate and late preterm infants. Am. J. Perinatol. 33, 305–317 (2016).

    PubMed  Google Scholar 

  38. Kirschbaum, C. & Hellhammer, D. Response variability of salivary cortisol under psychological stimulation. J. Clin. Chem. Clin. Biochem. 27, 237 (1989).

    CAS  PubMed  Google Scholar 

  39. Kirschbaum, C. & Hellhammer, D. H. Salivary cortisol in psychoneuroendocrine research: recent developments and applications. Psychoneuroendocrinology 19, 313–333 (1994).

    CAS  PubMed  Google Scholar 

  40. Tronick, E. & Lester, B. M. Grandchild of the NBAS: the NICU Network Neurobehavioral Scale (NNNS). J. Child Adolesc. Psychiatr. Nurs. 26, 193–203 (2013).

    PubMed  Google Scholar 

  41. Maccani, J. Z. J. et al. Placental DNA methylation related to both infant toenail mercury and adverse neurobehavioral outcomes. Environ. Health Perspect. 123, 723–729 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang, X. et al. The association of prenatal exposure to intensive traffic with early preterm infant neurobehavioral development as reflected by the NICU Network Neurobehavioral Scale (NNNS). Environ. Res. https://doi.org/10.1016/j.envres.2020.109204 (2020).

  43. Stroustrup, A. et al. Neonatal intensive care unit phthalate exposure and preterm infant neurobehavioral performance. PLoS ONE 13, e0193835 (2018).

  44. Smith, L. M. et al. Prenatal methamphetamine use and neonatal neurobehavioral outcome. Neurotoxicol. Teratol. 30, 20–28 (2008).

    CAS  PubMed  Google Scholar 

  45. Velez, M. L., Jansson, L. M., Schroeder, J. & Williams, E. Prenatal methadone exposure and neonatal neurobehavioral functioning. Pediatr. Res. 66, 704–709 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bello, G. A. et al. Extending the distributed lag model framework to handle chemical mixtures. Environ. Res. 156, 253–264 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Gennings, C. et al. Lagged WQS regression for mixtures with many components. Environ. Res. https://doi.org/10.1016/j.envres.2020.109529 (2020).

  48. Gasparrini, A., Armstrong, B. & Kenward, M. G. Distributed lag non‐linear models. Stat. Med. 29, 2224–2234 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Gasparrini, A. & Armstrong, B. Time series analysis on the health effects of temperature: advancements and limitations. Environ. Res. 110, 633–638 (2010).

    CAS  PubMed  Google Scholar 

  50. Chen, Y.-H., Ferguson, K. K., Meeker, J. D., McElrath, T. F. & Mukherjee, B. Statistical methods for modeling repeated measures of maternal environmental exposure biomarkers during pregnancy in association with preterm birth. Environ. Health 14, 9 (2015).

    PubMed  PubMed Central  Google Scholar 

  51. Custodio, R. J. et al. The emergence of the cortisol circadian rhythm in monozygotic and dizygotic twin infants: the twin-pair synchrony. Clin. Endocrinol. 66, 192–197 (2007).

    CAS  Google Scholar 

  52. Boukydis, C. Z., Bigsby, R. & Lester, B. M. Clinical use of the neonatal intensive care unit network neurobehavioral scale. Pediatrics 113, 679–689 (2004).

    PubMed  Google Scholar 

  53. Maselko, J. et al. Child mental health and maternal depression history in Pakistan. Soc. Psychiatry Psychiatr. Epidemiol. 51, 49–62 (2016).

    PubMed  Google Scholar 

  54. McRae, K., Ochsner, K. N., Mauss, I. B., Gabrieli, J. J. D. & Gross, J. J. Gender differences in emotion regulation: an fMRI study of cognitive reappraisal. Group Process Intergroup Relat. 11, 143–162 (2008).

    PubMed  PubMed Central  Google Scholar 

  55. Vigil, J. M. A socio-relational framework of sex differences in the expression of emotion. Behav. Brain Sci. 32, 375–390 (2009).

    PubMed  Google Scholar 

  56. Schreier, H. M. et al. Mercury and psychosocial stress exposure interact to predict maternal diurnal cortisol during pregnancy. Environ. Health 14, 28 (2015).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank John Smith, Shaliz Pourkaviani, and Mount Sinai NICU nurses for their assistance with data collection.

Funding

Funding for NICU-HEALTH came through pilot grants from the Passport Foundation, the Mount Sinai Children’s Environmental Health Center, a National Institute of Environmental Health Sciences (NIEHS) mentored award K23ES022268 to A.S., an NIEHS Center Core Grant P30ES023515, and the National Institutes of Health ECHO program UG3OD02332 and UH3OD023337.

Author information

Authors and Affiliations

  1. Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Xueying Zhang, Emily Spear, Hsiao-Hsien Leon Hsu, Chris Gennings & Annemarie Stroustrup

  2. Division of Neonatology, Department of Pediatrics, Cohen Children’s Medical Center, Zucker School of Medicine at Hofstra, Northwell Health, Queens, NY, USA

    Annemarie Stroustrup

Authors
  1. Xueying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emily Spear
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hsiao-Hsien Leon Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chris Gennings
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Annemarie Stroustrup
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: X.Z., H.-H.L.H., C.G., A.S. Drafting the article or revising it critically for important intellectual content: X.Z., A.S. Final approval of the version to be published: E.S., H.-H.L.H., C.G.

Corresponding author

Correspondence to Xueying Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All participants provided written informed consent prior to enrollment in the NICU Hospital Exposures and Long-Term Health (NICU-HEALTH) study. The study was approved by the Program for the Protection of Research Subjects at the Icahn School of Medicine at Mount Sinai (IRB-16-01139; GCO#12-0332).

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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Spear, E., Hsu, HH.L. et al. NICU-based stress response and preterm infant neurobehavior: exploring the critical windows for exposure. Pediatr Res (2022). https://doi.org/10.1038/s41390-022-01983-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41390-022-01983-3

Search

Advanced search

Quick links