Prenatal Opioid Exposure and Risk for Adverse Brain and Motor Outcomes in Infants Born Premature.

OBJECTIVE: To compare brain magnetic resonance imaging (MRI) biomarkers and neurodevelopmental test scores in infants born preterm with and without prenatal opioid exposure (POE). STUDY DESIGN: We examined 395 preterm infants (≤32 weeks gestational age) who had term-equivalent brain MRIs, composite scores from the Bayley Scales of Infant and Toddler Development-III at 2 years corrected age, and POE data. MRI parameters included total/regional brain volumes and severe punctate white matter lesions (PWMLs). We conducted bivariable analysis and multivariable logistic regression analyses. RESULTS: The mean ± SD gestational age was 29.3 ± 2.5 weeks; 35 (8.9%) had POE and 20 (5.1%) had severe PWML. Compared with unexposed infants, those with POE exhibited higher rates of severe PWML (17.1% vs 3.9%, respectively; P = .002); findings remained significant with an OR of 4.16 (95% CI, 1.26-13.68) after adjusting for confounders. On mediation analysis, the significant relationship between POE and severe PWML was not indirectly mediated through preterm birth/gestational age (OR, 0.93; 95% CI, 0.78-1.10), thus suggesting the association was largely driven by a direct adverse effect of POE on white matter. In multivariable analyses, POE was associated with a significantly lower score by -6.2 (95% CI, -11.8 to -0.6) points on the Bayley Scales of Infant and Toddler Development-III Motor subscale compared with unexposed infants. CONCLUSIONS: POE was associated with severe PWML; this outcome may be a direct effect of POE rather than being mediated by premature birth. POE was also associated with worse motor development. Continued follow-up to understand the long-term effects of POE is warranted.

Associations Between Early Structural Magnetic Resonance Imaging, Hammersmith Infant Neurological Examination, and General Movements Assessment in Infants Born Very Preterm.

OBJECTIVE: To evaluate the prevalence and associations between structural magnetic resonance imaging (sMRI) injury/abnormality at term-equivalent age and absent fidgety General Movements Assessment (GMA) and abnormal Hammersmith Infant Neurological Examination (HINE) scores among infants born very preterm at 3-4 months of corrected age. STUDY DESIGN: This prospective cohort study enrolled 392 infants born ≤2 weeks of gestation from 5 neonatal intensive care units in the greater Cincinnati area between September 2016 and October 2019. Infants completed sMRI at term-equivalent age and GMA and HINE at 3-4 months of corrected age. All assessors were blinded. RESULTS: Of 392 infants, 375 (96%) had complete data. Of these, 44 (12%) exhibited moderate or severe brain abnormalities, 17 (4.5%) had abnormal GMA, and 77 (20.3%) had abnormal HINE. Global and regional abnormality scores on sMRI were significantly correlated with GMA (R2 range 0.05-0.17) and HINE at 3-4 months of corrected age (R2 range 0.01-0.17). These associations remained significant in multivariable analyses after adjusting for gestational age and sex. There was a significant but low correlation (R2 0.14) between GMA and HINE. CONCLUSIONS: We observed a low prevalence of moderate or severe brain abnormalities in survivors born very preterm in this geographically defined cohort. The much greater prevalence of abnormal motor examination on the HINE compared with GMA and their low correlation suggests that these tests evaluate different constructs and, thus, should be used in combination with sMRI rather than interchangeably.

Perinatal Risk and Protective Factors in the Development of Diffuse White Matter Abnormality on Term-Equivalent Age Magnetic Resonance Imaging in Infants Born Very Preterm.

OBJECTIVE: To identify perinatal clinical diseases and treatments that are associated with the development of objectively diagnosed diffuse white matter abnormality (DWMA) on structural magnetic resonance imaging (MRI) at term-equivalent age in infants born very preterm. STUDY DESIGN: A prospective cohort of 392 infants born very preterm (≤32 weeks of gestational age) was enrolled from 5 level III/IV neonatal intensive care units between September 2016 and November 2019. MRIs of the brain were collected at 39 to 45 weeks of postmenstrual age to evaluate DWMA volume. A predefined list of pertinent maternal characteristics, pregnancy/delivery data, and neonatal intensive care unit data were collected for enrolled patients to identify antecedents of objectively diagnosed DWMA. RESULTS: Of the 392 infants in the cohort, 377 (96%) had high-quality MRI data. Their mean (SD) gestational age was 29.3 (2.5) weeks. In multivariable linear regression analyses, pneumothorax (P = .027), severe bronchopulmonary dysplasia (BPD) (P = .009), severe retinopathy of prematurity (P < .001), and male sex (P = .041) were associated with increasing volume of DWMA. The following factors were associated with decreased risk of DWMA: postnatal dexamethasone therapy for severe BPD (P = .004), duration of caffeine therapy for severe BPD (P = .009), and exclusive maternal milk diet at neonatal intensive care unit discharge (P = .049). CONCLUSIONS: Severe retinopathy of prematurity and BPD exhibited the strongest adverse association with development of DWMA. We also identified treatments and nutritional factors that appear protective against the development of DWMA that also have implications for the clinical care of infants born very preterm.

Objectively Diagnosed Diffuse White Matter Abnormality at Term Is an Independent Predictor of Cognitive and Language Outcomes in Infants Born Very Preterm.

OBJECTIVE: To externally validate the independent value of objectively diagnosed diffuse white matter abnormality (DWMA; also known as diffuse excessive high signal intensity) volume to predict neurodevelopmental outcomes in very preterm infants (≤31 weeks of gestational age). STUDY DESIGN: A prospective, multicenter, regional population-based cohort study in 98 very preterm infants without severe brain injury on magnetic resonance imaging (MRI). DWMA volume was diagnosed objectively on structural MRI at term-equivalent age using our published algorithm. Multivariable linear regression was used to assess the value of DWMA volume to predict cognitive and language scores on the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 2 years corrected age. RESULTS: Of the infants who returned for follow-up (n = 74), the mean (SD) gestational age was 28.2 (2.4) weeks, and 42 (56.8%) were boys. In bivariable analyses, DWMA volume was a significant predictor of Bayley-III cognitive and language scores. In multivariable analyses, controlling for known predictors of Bayley-III scores (ie, socioeconomic status, gestational age, sex, and global brain abnormality score), DWMA volume remained a significant predictor of cognitive (P < .001) and language (P = .04) scores at 2 years. When dichotomized, objectively diagnosed severe DWMA was a significant predictor of cognitive and language impairments, whereas visual qualitative diagnosis of DWMA was a poor predictor. CONCLUSIONS: In this multicenter, prospective cohort study, we externally validated our previous findings that objectively diagnosed DWMA is an independent predictor of cognitive and language development in very preterm infants. We also demonstrated again that visually-diagnosed DWMA is not predictive of neurodevelopmental outcomes.

Antecedents of Objectively Diagnosed Diffuse White Matter Abnormality in Very Preterm Infants.

BACKGROUND: Diffuse white matter abnormality (diffuse excessive high signal intensity) is the most common finding on structural brain magnetic resonance imaging (MRI) at term-equivalent age in very preterm infants. Yet, there remains a large gap in our understanding of the etiology of diffuse white matter abnormality. Our objective was to evaluate perinatal and neonatal inflammation-associated antecedents of diffuse white matter abnormality on MRI. METHODS: We prospectively enrolled 110 very preterm infants born at ≤31 weeks gestational age and collected data on multiple perinatal/neonatal exposures, especially inflammation initiating-illnesses. We performed structural MRI at term-equivalent age and quantified the volume of diffuse white matter abnormality objectively. Multivariable regression was used to identify clinical antecedents of diffuse white matter abnormality. RESULTS: The mean (S.D.) birth gestational age of the final study sample of 98 very preterm infants was 28.3 (2.5) weeks. Multiple inflammation initiating-illnesses were associated with diffuse white matter abnormality in univariate analyses. In multivariable linear regression analyses controlling for gestational age, severe retinopathy of prematurity (P < 0.001) and bronchopulmonary dysplasia (P = 0.006) were independent risk factors, whereas maternal treatment with 17-hydroxyprogesterone (P < 0.001) was protective of later development of objectively quantified diffuse white matter abnormality. CONCLUSIONS: We identified several perinatal and neonatal antecedent clinical factors associated with diffuse white matter abnormality. Although we found some support for inflammation as a common underlying mechanism, larger studies are needed to validate inflammation as a potential common pathway to the development of diffuse white matter abnormality in very preterm infants.