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.
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.
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.
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.
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.
This is a preview of subscription content, access via your institution
Subscribe to Journal
Get full journal access for 1 year
only $9.15 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Moster, D., Lie, R. T. & Markestad, T. Long-term medical and social consequences of preterm birth. N. Engl. J. Med. 359, 262–273 (2008).
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).
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).
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).
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).
Hirvonen, M. et al. Cerebral palsy among children born moderately and late preterm. Pediatrics 134, e1584–e1593 (2014).
Sun, Y. et al. Gestational age, birth weight, intrauterine growth, and the risk of epilepsy. Am. J. Epidemiol. 167, 262–270 (2007).
Crump, C., Sundquist, K., Winkleby, M. A. & Sundquist, J. Preterm birth and risk of epilepsy in Swedish adults. Neurology 77, 1376–1382 (2011).
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).
Li, W. et al. Do premature and postterm birth increase the risk of epilepsy? An updated meta-analysis. Epilepsy Behav. 97, 83–91 (2019).
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).
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).
Hüppi, P. S. et al. Quantitative magnetic resonance imaging of brain development in premature and mature newborns. Ann. Neurol. 43, 224–235 (1998).
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).
Woodward, L. J. et al. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N. Engl. J. Med. 355, 685–694 (2006).
Horber, V. et al. The origin of the cerebral palsies: contribution of population-based neuroimaging data. Neuropediatrics 51, 113–119 (2020).
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).
Simon, N. P. Long-term neurodevelopmental outcome of asphyxiated newborns. Clin. Perinatol. 26, 767–778 (1999).
Knudsen, L. B. & Olsen, J. The Danish medical birth registry. Dan. Med. Bull. 45, 320–323 (1998).
Maršál, K. et al. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr. 85, 843–848 (1996).
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).
Rasmussen, H. M. et al. The Danish cerebral palsy follow-up program. Clin. Epidemiol. 8, 457–460 (2016).
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).
R Core Team. R: A Language and Environment for Statistical Computing, (R Foundation for Statistical Computing, Vienna, Austria, 2020). https://www.R-project.org
Jensen, V. M. & Rasmussen, A. W. Danish education registers. Scand. J. Public Health 39, 91–94 (2011).
Christensen, J., Vestergaard, M., Olsen, J. & Sidenius, P. Validation of epilepsy diagnoses in the Danish National Hospital Register. Epilepsy Res. 75, 162–170 (2007).
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).
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).
Tu, Y.-F. et al. Epilepsy occurrence after neonatal morbidities in very preterm infants. Epilepsia 60, 2086–2094 (2019).
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).
Höfler, M. Causal inference based on counterfactuals. BMC Med. Res. Methodol. 5, 28 (2005).
This study was supported by the Elsass Foundation (19-3-0283). The funding parties did not have any involvement in the study.
The authors declare no competing interests.
No patient consent was required for this study.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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