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The effect of gestational age on major neurodevelopmental disorders in preterm infants

Abstract

Background

Preterm infants have an increased risk of neurodevelopmental disorders. We established a direct quantitative comparison of the association between the degree of prematurity and three different neurodevelopmental disorders.

Methods

In this cohort study, we combined data from 995,498 children in the Danish Medical Birth Register, from birth years 1997–2013, with information on cerebral palsy, epilepsy, and special educational needs. We estimated the gestational week-specific prevalence and risk for each of the disorders.

Results

The risk ratio of cerebral palsy at gestational weeks 21–24, compared to term birth, was more than ten times higher than for the two other disorders. The prevalence of epilepsy and special educational needs declined almost parallel, with 9.2% (4.6%–13.5%) and 12.5% (11.2%–13.7%), respectively, per week of gestation toward term birth. Cerebral palsy did not decline similarly: from gestational weeks 21–24 until week 29 the prevalence declined insignificantly by 0.6% (−11.1%–11.0%) per week; whereas from week 29 until term, the prevalence declined markedly by 36.7% (25.9%–45.9%) per week.

Conclusions

The prevalence and risk of cerebral palsy are affected differently by the degree of prematurity compared with epilepsy and special educational needs, possibly reflecting important differences in cerebral pathophysiology.

Impact

  • For each week of gestation toward term birth, there was a clear log-linear decline in the prevalence of early childhood epilepsy and special educational needs.

  • In contrast, the risk of cerebral palsy was high at the earliest gestational age, and the prevalence did not decline significantly until gestational week 29, from where it declined notably by nearly 40% for each week of gestation until term birth.

  • Our results indicate important differences in the pathophysiological processes that associate preterm birth with these three neurodevelopmental disorders.

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Fig. 1: Study population.
Fig. 2: Prevalence (per 1000) with 95% confidence intervals for each gestational age group for the three disorders of cerebral palsy, epilepsy, and special educational needs.
Fig. 3: Risk ratio with 95% confidence intervals for each gestational age group associated with the three disorders of cerebral palsy, epilepsy, and special educational needs.

References

  1. Moster, D., Lie, R. T. & Markestad, T. Long-term medical and social consequences of preterm birth. N. Engl. J. Med. 359, 262–273 (2008).

    Article  CAS  Google Scholar 

  2. Pascal, A. et al. Neurodevelopmental outcome in very preterm and very-low-birthweight infants born over the past decade: a meta-analytic review. Dev. Med. Child Neurol. 60, 342–355 (2018).

    Article  Google Scholar 

  3. Himpens, E. et al. Prevalence, type, distribution, and severity of cerebral palsy in relation to gestational age: A meta-analytic review. Dev. Med. Child Neurol. 50, 334–340 (2008).

    Article  CAS  Google Scholar 

  4. Oskoui, M. et al. An update on the prevalence of cerebral palsy: a systematic review and meta-analysis. Dev. Med. Child Neurol. 55, 509–519 (2013).

    Article  Google Scholar 

  5. Trønnes, H. et al. Risk of cerebral palsy in relation to pregnancy disorders and preterm birth: a national cohort study. Dev. Med. Child Neurol. 56, 779–785 (2014).

    Article  Google Scholar 

  6. Hirvonen, M. et al. Cerebral palsy among children born moderately and late preterm. Pediatrics 134, e1584–e1593 (2014).

    Article  Google Scholar 

  7. Sun, Y. et al. Gestational age, birth weight, intrauterine growth, and the risk of epilepsy. Am. J. Epidemiol. 167, 262–270 (2007).

    Article  Google Scholar 

  8. Crump, C., Sundquist, K., Winkleby, M. A. & Sundquist, J. Preterm birth and risk of epilepsy in Swedish adults. Neurology 77, 1376–1382 (2011).

    Article  Google Scholar 

  9. Hirvonen, M. et al. The incidence and risk factors of epilepsy in children born preterm: a nationwide register study. Epilepsy Res. 138, 32–38 (2017).

    Article  Google Scholar 

  10. Li, W. et al. Do premature and postterm birth increase the risk of epilepsy? An updated meta-analysis. Epilepsy Behav. 97, 83–91 (2019).

    Article  Google Scholar 

  11. MacKay, D. F., Smith, G. C. S., Dobbie, R. & Pell, J. P. Gestational age at delivery and special educational need: retrospective cohort study of 407,503 school children. PLoS Med. 7, e1000289 (2010).

    Article  Google Scholar 

  12. Wiingreen, R., Greisen, G., Svensson, J. & Hansen, B. M. Low gestational age at birth and difficulties in school—a matter of ‘dose’. PLoS ONE. 13, e0198482 (2018).

  13. Hüppi, P. S. et al. Quantitative magnetic resonance imaging of brain development in premature and mature newborns. Ann. Neurol. 43, 224–235 (1998).

    Article  Google Scholar 

  14. Back, S. A. Perinatal white matter injury: the changing spectrum of pathology and emerging insights into pathogenetic mechanisms. Ment. Retard. Dev. Disabil. Res. Rev. 12, 129–140 (2006).

    Article  Google Scholar 

  15. Woodward, L. J. et al. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N. Engl. J. Med. 355, 685–694 (2006).

    Article  CAS  Google Scholar 

  16. Horber, V. et al. The origin of the cerebral palsies: contribution of population-based neuroimaging data. Neuropediatrics 51, 113–119 (2020).

    Article  Google Scholar 

  17. Stoknes, M. et al. The effects of multiple pre- and perinatal risk factors on the occurrence of cerebral palsy. A Norwegian register based study. Eur. J. Paediatr. Neurol. 16, 56–63 (2012).

    Article  Google Scholar 

  18. Simon, N. P. Long-term neurodevelopmental outcome of asphyxiated newborns. Clin. Perinatol. 26, 767–778 (1999).

    Article  CAS  Google Scholar 

  19. Knudsen, L. B. & Olsen, J. The Danish medical birth registry. Dan. Med. Bull. 45, 320–323 (1998).

    CAS  PubMed  Google Scholar 

  20. Maršál, K. et al. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr. 85, 843–848 (1996).

    Article  Google Scholar 

  21. Uldall, P., Michelsen, S. I., Topp, M. & Madsen, M. The Danish Cerebral Palsy Registry. A registry on a specific impairment. Dan. Med. Bull. 48, 161–163 (2001).

    CAS  PubMed  Google Scholar 

  22. Rasmussen, H. M. et al. The Danish cerebral palsy follow-up program. Clin. Epidemiol. 8, 457–460 (2016).

    Article  Google Scholar 

  23. Madsen, M. et al. The Danish National Hospital Register: a valuable source of data for modern health sciences. Dan. Med. Bull. 46, 263–268 (1999).

  24. R Core Team. R: A Language and Environment for Statistical Computing, (R Foundation for Statistical Computing, Vienna, Austria, 2020). https://www.R-project.org

  25. Jensen, V. M. & Rasmussen, A. W. Danish education registers. Scand. J. Public Health 39, 91–94 (2011).

    Article  Google Scholar 

  26. Christensen, J., Vestergaard, M., Olsen, J. & Sidenius, P. Validation of epilepsy diagnoses in the Danish National Hospital Register. Epilepsy Res. 75, 162–170 (2007).

    Article  Google Scholar 

  27. Larsen, M. L. et al. Continuing decline in the prevalence of cerebral palsy in Denmark for birth years 2008–2013. Eur. J. Paediatr. Neurol. 30, 155–161 (2021).

    Article  Google Scholar 

  28. Back, S. A. et al. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J. Neurosci. 21, 1302–1312 (2001).

    Article  CAS  Google Scholar 

  29. Tu, Y.-F. et al. Epilepsy occurrence after neonatal morbidities in very preterm infants. Epilepsia 60, 2086–2094 (2019).

    Article  CAS  Google Scholar 

  30. Carrasco, M. & Stafstrom, C. E. How early can a seizure happen? Pathophysiological Considerations of extremely premature infant brain development. Dev. Neurosci. 40, 417–436 (2019).

    Article  Google Scholar 

  31. Höfler, M. Causal inference based on counterfactuals. BMC Med. Res. Methodol. 5, 28 (2005).

    Article  Google Scholar 

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Acknowledgements

This study was supported by the Elsass Foundation (19-3-0283). The funding parties did not have any involvement in the study.

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Contributions

M.L.L., R.W., A.J., and G.G. created the concept and design. M.L.L., R.W., G.R., B.L., B.M.H., C.E.H.-H., and G.G. were a substantial part of data acquisition. M.L.L., R.W., and A.J. analyzed the data. M.L.L. and G.G. performed data interpretation. M.L.L., R.W., and G.G. created the original draft. All authors participated in critical reviewing and editing of the final version. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Mads L. Larsen.

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The authors declare no competing interests.

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No patient consent was required for this study.

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Larsen, M.L., Wiingreen, R., Jensen, A. et al. The effect of gestational age on major neurodevelopmental disorders in preterm infants. Pediatr Res 91, 1906–1912 (2022). https://doi.org/10.1038/s41390-021-01710-4

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