Neonatal Cranial Ultrasound Findings among Infants Born Extremely Preterm: Associations with Neurodevelopmental Outcomes at 10 Years of Age

Heather Campbell, Jennifer Check, Karl C K Kuban, Alan Leviton, Robert M Joseph, Jean A Frazier, Laurie M Douglass, Kyle Roell, Elizabeth N Allred, Lynn Ansley Fordham, Stephen R Hooper, Hernan Jara, Nigel Paneth, Irina Mokrova, Hongyu Ru, Hudson P Santos Jr, Rebecca C Fry, T Michael O'Shea

J Pediatr. 2021 Oct;237:197-205.e4. doi: 10.1016/j.jpeds.2021.05.059. Epub 2021 Jun 4. PMID: 34090894; PMCID: PMC8478718.

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Ultrasound-identified white matter damage (WMD) without intraventricular hemorrhage (IVH) was associated with an increased risk of cognitive impairment (OR 3.5, 95% CI 1.7, 7.4), cerebral palsy (OR 14.3, 95% CI 6.5, 31.5), and epilepsy (OR 6.9; 95% CI 2.9, 16.8). Similar associations were found for WMD accompanied by IVH. Isolated IVH was not significantly associated these outcomes. Among children born extremely preterm, CUS abnormalities, particularly those indicative of WMD, are predictive of neurodevelopmental impairments at 10 years of age. The strongest associations were found with cerebral palsy.

Comparing the Predictivity of Human Placental Gene, microRNA, and CpG Methylation Signatures in Relation to Perinatal Outcomes

Jeliyah Clark, Vennela Avula, Caroline Ring, Lauren A Eaves, Thomas Howard, Hudson P Santos, Lisa Smeester, Jacqueline T Bangma, Thomas Michael O'Shea, Rebecca C Fry, Julia E Rager

Toxicol Sci. 2021 Sep 28;183(2):269-284. doi: 10.1093/toxsci/kfab089. PMID: 34255065; PMCID: PMC8478332.

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This study evaluated mRNA and microRNA (miRNA) expression and cytosine-guanine dinucleotide (CpG) methylation signatures in human placental tissues in relation to birth weight, placenta weight, placental damage, and placental inflammation. The following hypotheses were tested: (1) different molecular signatures will demonstrate varying levels of predictivity towards perinatal outcomes, and (2) these signatures will show disruptions from an example exposure (ie, cadmium) known to elicit perinatal toxicity. Epigenomic signatures (ie, miRNA and CpG methylation) consistently demonstrated the highest levels of predictivity; top-ranking predictors included miRNAs involved in injury and inflammation. These top-ranking miRNA predictors were analyzed in a separate pregnancy cohort and related to cadmium. Key predictive miRNAs demonstrated altered expression in association with cadmium exposure, including miR-210, known to impact placental cell growth, blood vessel development, and fetal weight.

Systemic Inflammation in the First 2 Weeks After Birth as a Determinant of Physical Growth Outcomes in Hospitalized Infants With Extremely Low Gestational Age

Mandy B Belfort, Sara E Ramel, Camilia R Martin, Raina Fichorova, Karl C K Kuban, Timothy Heeren, Rebecca C Fry, T Michael O'Shea

J Pediatr. 2021 Sep 8:S0022-3476(21)00879-9. doi: 10.1016/j.jpeds.2021.09.006. Epub ahead of print. PMID: 34508750.

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The goal of this study was to examine associations of systemic inflammation with growth outcomes at neonatal intensive care unit (NICU) discharge/transfer among infants with extremely low gestational ages. Infants with CRP elevation on day 7 had lower weights at discharge/transfer (-0.17 z-scores, 95% CI -0.27, -0.06) than infants without CRP elevation; with similar results on day 14. Infants with CRP elevation on day 14 were also shorter (-0.21 length z-scores, 95% CI -0.38, -0.04), and had smaller head circumferences (-0.18 z-scores, 95% CI -0.33, -0.04) at discharge/transfer. IL-6 elevation on day 14 was associated with lower weight (-0.12, 95% CI -0.22, -0.02); IL-6 elevation on day 7 was associated with shorter length (-0.27, 95% CI -0.43, -0.12). TNF-∝ and IL-8 elevation on day 14 were associated with lower weight at discharge/transfer. Postnatal systemic inflammation may contribute to impaired nutrient accretion during a critical period in development in infants with extremely low gestational ages.

Prenatal tobacco smoke exposure and neurological impairment at 10 years of age among children born extremely preterm: a prospective cohort

K K Venkatesh, A Leviton, R N Fichorova, R M Joseph, L M Douglass, J A Frazier, Kck Kuban, H P Santos Jr, R C Fry, T M O'Shea

BJOG. 2021 Sep;128(10):1586-1597. doi: 10.1111/1471-0528.16690. Epub 2021 Apr 6. PMID: 33682301.

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Of 1200 ELGAN study survivors, 856 were assessed at 10 years of age with neurological outcomes, of whom 14% (118/856) had active tobacco exposure during pregnancy and 24% (207/852) had passive tobacco exposure. Compared with children who were not exposed prenatally to tobacco, children exposed to active tobacco use during pregnancy had a higher risk of epilepsy (14% versus 5%; adjusted relative risk: 1.68, 95% CI 1.45-1.92). This risk remained after adjustment for gestational age at delivery and clinical subtype of preterm birth. Prenatal tobacco smoke exposure was not associated with other assessed neurological outcomes, including cerebral palsy and multiple measures of cognitive impairment.Among children born extremely preterm, prenatal active tobacco smoke exposure was associated with an increased risk of epilepsy at 10 years of life.

Pre-pregnancy BMI-associated miRNA and mRNA expression signatures in the placenta highlight a sexually-dimorphic response to maternal underweight status

Jeliyah Clark, Lauren A Eaves, Adriana R Gaona, Hudson P Santos Jr, Lisa Smeester, Jacqueline T Bangma, Julia E Rager, T Michael O'Shea, Rebecca C Fry

Sci Rep. 2021 Aug 3;11(1):15743. doi: 10.1038/s41598-021-95051-1. PMID: 34344912; PMCID: PMC8333418.

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Genome-wide mRNA and miRNA expression levels were assessed in the placentas of infants born extremely preterm. Differences in expression were evaluated according to pre-pregnancy BMI status (1) overall and (2) in male and female placentas separately. Overall, 719 mRNAs were differentially expressed in relation to underweight status. Unexpectedly, no genes were differentially expressed in relation to overweight or obese status. In male placentas, 572 mRNAs were associated with underweight status, with 503 (70%) overlapping genes identified overall. Notably, 43/572 (8%) of the mRNAs associated with underweight status in male placentas were also gene targets of two miRNAs (miR-4057 and miR-128-1-5p) associated with underweight status in male placentas. Pathways regulating placental nutrient metabolism and angiogenesis were among those enriched in mRNAs associated with underweight status in males.

Development of the genomic inflammatory index (GII) to assess key maternal antecedents associated with placental inflammation.

Kirsi S Oldenburg, Lauren A Eaves, Lisa Smeester, Hudson P Santos, T Michael O'Shea, Rebecca C Fry

Placenta. 2021 Aug;111:82-90. doi: 10.1016/j.placenta.2021.06.010. Epub 2021 Jun 18. PMID: 34182215.

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The Genomic Inflammatory Index demonstrated a nine-fold difference across subjects and displayed positive trends with other indicators of placental inflammation. Significant differences in the GII were observed for race where women who self-identified as Black displayed higher levels of placental inflammation than those who self-identified as White women (p < 0.001). Additionally, married Black women showed reduced placental inflammation compared to those who were unmarried (beta value: 0.828, p-value: 0.032). Placentas from women who were treated with steroids during the delivery of the infant displayed higher GII levels than those who were not (p = 0.023). Overall, the GII demonstrated an association between various perinatal factors and placental inflammation. It is anticipated that the GII will provide a novel genomics tool for quantifying placental inflammation, allowing for further investigation of causes, and ultimately the prevention, of inflammation in the placenta.

Changes in Neurodevelopmental Outcomes From Age 2 to 10 Years for Children Born Extremely Preterm

Genevieve L Taylor, Robert M Joseph, Karl C K Kuban, Laurie M Douglass, Jeff Laux, Bree Andrews, Rebecca C Fry, Wayne A Price, Thomas M O'Shea

Pediatrics. 2021 May;147(5):e2020001040. doi: 10.1542/peds.2020-001040. Epub 2021 Apr 6. PMID: 33824183; PMCID: PMC8086004.

PubMed Link

Among children classified as having moderate to severe neurodevelopmental impairment (NDI) at 2 years, 63% had none to mild NDI at 10 years; among children classified as having profound NDI at 2 years, 36% had none to mild NDI at 10 years. We fond minimal to fair agreement between NDI at 2 and 10 years. NDI in infancy, as defined in this study, only weakly predicts NDI in middle childhood. For the parents at risk for delivery of an extremely preterm infant, a hopeful message can be taken from our findings that one-third of surviving children classified as having profound NDI and nearly two-thirds of those classified as having moderate to severe NDI at 2 years had none to mild NDI at 10 years.

Anxiety and Depression Correlates at Age 10 in Children Born Extremely Preterm

Phoebe S Moore, Irina Mokrova, Jean A Frazier, Robert M Joseph, Hudson P Santos, Yael Dvir, Stephen R Hooper, T Michael O'Shea, Laurie M Douglass, Karl C K Kuban

J Pediatr Psychol. 2021 Jan 4; jsaa118.

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Anxiety and depression rates are elevated in prematurely-born children and adolescents. This prospective study examines demographic, academic, and physical health correlates of anxiety and depression symptoms in a sample of 10-y-o children born EP. Participants were 889 (51.2% male; 62.3% White). Level of prematurity was significantly related to both parent and teacher reports of anxiety. Public health insurance and IEP were associated with both parent and teacher reports of depression. Hispanic ethnicity, public insurance, IEP status, and asthma were significantly associated with both parent-reported anxiety and depression. Gross motor impairment was associated with parent-reported anxiety and teacher-reported depression. Child obesity was associated with teacher reports of anxiety, while male sex was significantly related to teacher reports of depression.

Evidence for the placenta-brain axis: multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm

Hudson P Santos Jr, Arjun Bhattacharya, Robert M Joseph, Lisa Smeester, Karl C K Kuban, Carmen J Marsit, T Michael O'Shea, Rebecca C Fry

Mol Autism. 2020 Dec 11;11(1):97.

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We examined associations between placental transcriptomic & epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the ELGAN cohort. Genes with important roles in neuro-development and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted IQ and social function, explaining ~ 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed sign positive and negative associations with ASD case-control status. Aggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born EP, suggesting that traits within the placenta-brain axis may be omnigenic.

Placental programming, perinatal inflammation, and neurodevelopment impairment among those born extremely preterm

Jacqueline T. Bangma, Hadley Hartwell, Hudson P. Santos Jr., T. Michael O’Shea & Rebecca C. Fry

Pediatr Res. 2020 Nov 12;1-10.

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Individuals born EP are at significant risk for impaired neurodevelopment. After discharge from the NICU, associations between child’s well-being and factors in the home and social environment become increasingly apparent. We review early life predictors of inter-individual differences in later life neurodevelopment among those born EP. Among biological mechanisms that mediate relationships between early life predictors and later neurodevelopmental outcomes, we highlight evidence for disrupted placental processes, regulated at least in part via epigenetic mechanisms, as well as perinatal inflammation. In relation to these mechanisms, we focus on four prenatal antecedents of impaired neurodevelopment, namely, (1) fetal growth restriction, (2) maternal obesity, (3) placental microorganisms, and (4) socioeconomic adversity. The findings highlighted here may inform efforts to detect and prevent adverse outcomes in infants born extremely preterm.