MRI Findings in Prematurely-Born Adolescents and Young Adults Who Screen Positive for Autism Spectrum Disorder.

IntroductionAutism spectrum disorder (ASD) is three to four times more common in prematurely-born children (<37 weeks' gestation) than term-born children.1Agrawal S. Rao S.C. Bulsara M.K. Patole S.K. Prevalence of autism spectrum disorder in preterm infants: a meta-analysis.Pediatrics. 2018; 142e20180134Crossref Scopus (118) Google Scholar The relationship between lower gestational age and ASD is independent of familial and environmental factors, suggesting a potential causal link.2Crump C. Sundquist J. Sundquist K. Preterm or early term birth and risk of autism.Pediatrics. 2021; 148e2020032300Crossref PubMed Scopus (10) Google Scholar Term-equivalent magnetic resonance imaging (MRI) findings do not reliably predict ASD in preterm infants,3Ure A.M. Treyvaud K. Thompson D.K. et al.Neonatal brain abnormalities associated with autism spectrum disorder in children born very preterm.Autism Res. 2016; 9: 543-552Crossref PubMed Scopus (28) Google Scholar and little is known about MRI findings in preterm children with ASD imaged later in childhood. To address this gap, we screened adolescents and young adults for ASD as part of a longitudinal cohort study of MRI in preterm infants4Miller S.P. Ferriero D.M. Leonard C. et al.Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome.J Pediatr. 2005; 147: 609-616Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar and compared neonatal and follow-up MRI findings by ASD screening status.MethodsParticipants were recruited from a prospective cohort of preterm infants <32 weeks' gestation admitted to University of California San Francisco from 1998 to 2018 (n = 451). Baseline characteristics were obtained from the medical records during the birth hospitalization by research nurses. The Social Communication Questionnaire and Social Responsiveness Scale, second edition, were sent to parents within two years of obtaining optional 10- to 18-year MRI (n = 61), of whom half responded. There were no differences in baseline characteristics and neonatal MRI findings between participants in this analysis and the parent cohort. ASD screen-positivity was defined as Social Communication Questionnaire score ≥15 and/or Social Responsiveness Scale, second edition, score ≥70 in males or ≥65 in females. The University of California San Francisco Institutional Review Board approved the study.One pediatric neuroradiologist (A.J.B.) reviewed all MRI scans unaware of history/outcome. Neonatal 1.5-T MRI scans were scored contemporaneously for white matter injury (WMI) using our published scoring system4Miller S.P. Ferriero D.M. Leonard C. et al.Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome.J Pediatr. 2005; 147: 609-616Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar and Papile grade intraventricular hemorrhage (IVH). Follow-up 3-T MRI was cross-sectionally evaluated for abnormalities in signal intensity, morphology, and volume. Descriptive statistics and logistic regression were used for planned comparisons between MRI findings and ASD screen-positivity.ResultsTen participants (33%) were classified as ASD screen-positive among 30 extremely- or very-preterm infants evaluated at median 16.5 years (interquartile range: 11.7 to 19.5) (Table 1). Six (20%) were positive on one ASD screener and four (13%) were positive on both; 3 out of 4 that were positive on both screeners carried a previous ASD diagnosis.TABLE 1Clinical Characteristics and MRI Findings by ASD Screening StatusClinical Characteristics and MRI FindingsASD Screen-PositiveNo (N = 20)Yes (N = 10)P ValueClinical Characteristics Gestational age (weeks), mean (S.D.)28.8 (2.2)27.8 (2.3)0.17 Birth weight (g), median (IQR)1008 (860, 1340)758 (650, 1260)0.19 Male, N (%)9 (45)5 (50)0.80 Maternal age (years), mean (S.D.)32.4 (7.8)28.3 (7.9)0.16 Prenatal steroids, N (%)18 (90)8 (80)0.27 Prenatal magnesium sulfate, N (%)8 (40)6 (60)0.44 Caesarean section, N (%)9 (45)6 (60)0.24 Apgar 5 min, median (IQR)8 (6.5, 8.5)7 (7, 9)0.11 Patent ductus arteriosus, N (%)5 (25)4 (40)0.41 Chronic lung disease, N (%)4 (20)4 (40)0.21 Necrotizing enterocolitis, N (%)1 (5)1 (10)0.51 Infection, N (%)9 (45)6 (60)0.70 Neonatal surgery, N (%)5 (25)5 (50)0.10 Retinopathy of prematurity, N (%)3 (15)2 (20)0.34Neonatal imaging findings Neonatal MRI obtained, N2010 Corrected age at MRI (weeks), median (IQR)34.9 (32.8, 35.6)34.8 (31.9, 37)0.91 Any abnormality1270.59 White matter injury, N (%)0.79None10 (50)4 (40)Mild5 (25)4 (40)Moderate/severe5 (25)2 (20) Intraventricular hemorrhage, N (%)1.0None14 (70)7 (70)Mild (Grade I/II)4 (20)2 (20)Moderate/Severe (Grade III/IV)2 (10)1 (10)Follow-up imaging findings Follow-up MRI obtained, N189 Age at MRI (years), median (IQR)12 (10.9, 14.4)14.4 (11.2, 15)0.23 Decreased white matter volume, N (%)3 (16.7)6 (66.7)0.026 Decreased cerebellar volume, N (%)02 (22.2)∗Both participants with decreased cerebellar volume also had decreased white matter volume.0.12Abbreviations:ASD = Autism spectrum disorderIQR = Interquartile rangeMRI = Magnetic resonance imaging∗ Both participants with decreased cerebellar volume also had decreased white matter volume. Open table in a new tab Abnormal neonatal MRI was more frequent in screen-positive participants (7 of 10 vs 12 of 20), but not significantly (Risk ratio [RR]: 1.17, 95% confidence interval [CI]: 0.68 to 2.0). IVH severity was similar in both groups; none had hydrocephalus. Punctate periventricular noncystic WMI was more common in screen-positive participants (6 of 10 vs 10 of 20). WMI severity was not associated with ASD screen-positivity (P = 0.79).Abnormal follow-up MRI was significantly more frequent in screen-positive participants (6 of 9 vs 3 to 18; RR: 4; 95% CI: 1.29 to 12.40). All abnormal follow-up scans had reduced supratentorial white matter volume (WMV); none had periventricular signal abnormality or gliosis, or cortical or deep gray abnormalities. Two screen-positive participants with decreased WMV also had decreased cerebellar volume with normal signal intensity.There were no screen-positive participants with normal neonatal and follow-up MRI (Table 2). Severity of neonatal WMI was not associated with diminished WMV in adolescence (P = 0.66). There was a trend toward more frequent IVH in those with decreased WMV (4 of 9 vs 3 of 18, P = 0.090). Moderate/severe WMI and/or moderate/severe IVH on neonatal MRI doubled the risk of decreased WMV on follow-up MRI (RR: 2.29, 95% CI: 0.85 to 6.18). Decreased WMV in adolescence was associated with increased odds of ASD screen-positivity (odds ratio: 10, 95% CI: 1.56 to 64.20, P = 0.015).TABLE 2Neonatal MRI Findings by Decreased White Matter Volume on Follow-Up MRINeonatal MRI FindingsDecreased White Matter Volume on Follow-Up MRINoYesP ValueAll participants189 Any abnormality, N (%)10 (56)6 (67)0.69 Severe abnormality∗Defined as moderate/severe WMI and/or Papile grade III/IV IVH., N (%)3 (17)4 (44)†One participant had moderate/severe IVH and moderate/severe WMI.0.18 White matter injury, N (%)0.66None9 (50)4 (44)Mild6 (33)2 (22)Moderate/severe3 (17)3 (33) Intraventricular hemorrhage, N (%)0.090None15 (83)5 (56)Mild (Grade I/II)3 (17)2 (22)Moderate/severe (Grade III/IV)02 (22)ASD screen-negative153 Any abnormality, N (%)7 (47)3 (100)0.22 Severe abnormality∗Defined as moderate/severe WMI and/or Papile grade III/IV IVH., N (%)3 (20)2 (67)0.17 White matter injury, N (%)0.56None9 (60)1 (33)Mild3 (20)1 (33)Moderate/severe3 (20)1 (33) Intraventricular hemorrhage, N (%)0.076None12 (80)1 (33)Mild (Grade I/II)3 (20)1 (33)Moderate/severe (Grade III/IV)01 (33)ASD screen-positive36 Any abnormality, N (%)3 (100)3 (50)0.46 Severe abnormality∗Defined as moderate/severe WMI and/or Papile grade III/IV IVH., N (%)02 (33)†One participant had moderate/severe IVH and moderate/severe WMI.0.50 White matter injury, N (%)0.14None03 (50)Mild3 (100)1 (17)Moderate/severe02 (33)Intraventricular hemorrhage, N (%)1.0None3 (100)4 (67)Mild (Grade I/II)01 (17)Moderate/severe (Grade III/IV)01 (17)Abbreviations:ASD = Autism spectrum disorderIVH = Intraventricular hemorrhageMRI = Magnetic resonance imagingWMI = White matter injury∗ Defined as moderate/severe WMI and/or Papile grade III/IV IVH.† One participant had moderate/severe IVH and moderate/severe WMI. Open table in a new tab DiscussionIn this exploratory study of adolescents and young adults born preterm, one-third screened positive for ASD and follow-up MRI commonly showed visibly diminished white matter in screen-positive participants. This finding is consistent with recently described white matter microstructural differences in prematurely-born adolescents with atypical development.5McNaughton R. Pieper C. Sakai O. et al.Quantitative MRI characterization of the extremely preterm brain at adolescence: atypical versus neurotypical developmental pathways.Radiology. 2022; 304: 419-428Crossref Scopus (2) Google Scholar In infants with ASD, white matter microstructure is reported to develop differently between six and 24 months.6Wolff J.J. Gu H. Gerig G. et al.Differences in white matter fiber tract development present from 6 to 24 months in infants with autism.Am J Psychiatry. 2012; 169: 589-600Crossref PubMed Scopus (466) Google Scholar Given the selective vulnerability of the preterm white matter, the preterm population provides a unique window to further study the relationship between white matter development and ASD. IntroductionAutism spectrum disorder (ASD) is three to four times more common in prematurely-born children (<37 weeks' gestation) than term-born children.1Agrawal S. Rao S.C. Bulsara M.K. Patole S.K. Prevalence of autism spectrum disorder in preterm infants: a meta-analysis.Pediatrics. 2018; 142e20180134Crossref Scopus (118) Google Scholar The relationship between lower gestational age and ASD is independent of familial and environmental factors, suggesting a potential causal link.2Crump C. Sundquist J. Sundquist K. Preterm or early term birth and risk of autism.Pediatrics. 2021; 148e2020032300Crossref PubMed Scopus (10) Google Scholar Term-equivalent magnetic resonance imaging (MRI) findings do not reliably predict ASD in preterm infants,3Ure A.M. Treyvaud K. Thompson D.K. et al.Neonatal brain abnormalities associated with autism spectrum disorder in children born very preterm.Autism Res. 2016; 9: 543-552Crossref PubMed Scopus (28) Google Scholar and little is known about MRI findings in preterm children with ASD imaged later in childhood. To address this gap, we screened adolescents and young adults for ASD as part of a longitudinal cohort study of MRI in preterm infants4Miller S.P. Ferriero D.M. Leonard C. et al.Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome.J Pediatr. 2005; 147: 609-616Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar and compared neonatal and follow-up MRI findings by ASD screening status.